U.S. patent application number 15/027137 was filed with the patent office on 2016-08-25 for 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles and a process for the preparation thereof.
This patent application is currently assigned to Council of Scientific & Industrial Research. The applicant listed for this patent is COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH. Invention is credited to Nitin Pal KALIA, Inshad Ali KHAN, Reddy Yempalla KUSHALAVA, Gurunadham MUNAGALA, Amit NARGOTRA, Vikrant Singh RAJPUT, Sanghapal Damodhar SAWANT, Parvinder Pal SINGH, Ram Asray VISHWAKARMA.
Application Number | 20160244462 15/027137 |
Document ID | / |
Family ID | 50771310 |
Filed Date | 2016-08-25 |
United States Patent
Application |
20160244462 |
Kind Code |
A1 |
SINGH; Parvinder Pal ; et
al. |
August 25, 2016 |
6-NITRO-2,3-DIHYDROIMIDAZO[2,1-b]OXAZOLES AND A PROCESS FOR THE
PREPARATION THEREOF
Abstract
The present invention relates to newer generation of triazoles,
tetrazoles, isoxazoles, urea and sulphonamide functionalities
containing 6-nitro-2, 3-dihydronitroimidazooxazoles agents of
formula 1, their method of preparation, and their use as drugs for
treating Mycobacterium tuberculosis, MDR-TB and XDR-TB either alone
or in combination with other anti-tubercular agents. In the present
invention, new generation 6-nitro-2, 3-dihydronitroimidazooxazoles
agents also show acceptable pharmacokinetic properties and
synergistic or additive effects with known anti-tubercular drugs.
##STR00001##
Inventors: |
SINGH; Parvinder Pal;
(Jammu, IN) ; MUNAGALA; Gurunadham; (Jammu,
IN) ; KUSHALAVA; Reddy Yempalla; (Jammu, IN) ;
KHAN; Inshad Ali; (Jammu, IN) ; KALIA; Nitin Pal;
(Jammu, IN) ; RAJPUT; Vikrant Singh; (Jammu,
IN) ; NARGOTRA; Amit; (Jammu, IN) ; SAWANT;
Sanghapal Damodhar; (Jammu, IN) ; VISHWAKARMA; Ram
Asray; (Jammu, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH |
New Delhi |
|
IN |
|
|
Assignee: |
Council of Scientific &
Industrial Research
New Delhi
IN
|
Family ID: |
50771310 |
Appl. No.: |
15/027137 |
Filed: |
March 31, 2014 |
PCT Filed: |
March 31, 2014 |
PCT NO: |
PCT/IN2014/000202 |
371 Date: |
April 4, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/06 20180101;
A61K 31/424 20130101; A61K 31/496 20130101; A61K 31/454 20130101;
A61K 45/06 20130101; A61K 31/4439 20130101; C07D 498/04 20130101;
A61K 31/5377 20130101 |
International
Class: |
C07D 498/04 20060101
C07D498/04; A61K 31/4439 20060101 A61K031/4439; A61K 45/06 20060101
A61K045/06; A61K 31/454 20060101 A61K031/454; A61K 31/5377 20060101
A61K031/5377; A61K 31/424 20060101 A61K031/424; A61K 31/496
20060101 A61K031/496 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 4, 2013 |
IN |
2954/DEL/2013 |
Claims
1. A compound of general formula 1 or pharmaceutically acceptable
salts thereof ##STR00219## wherein substituent `S` is selected from
the group consisting of formula Ia, Ib, Ic, IIa, IIb and IIc;
##STR00220## wherein, `G` is selected from the group consisting of
H, CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1; `Z` is selected from the
group consisting of O, S and NR.sub.2; `n` is any number from 0 to
2; `M` is selected from the group consisting of O, S, NR.sub.2 and
CR.sub.3R.sub.4; R, R.sub.1 and R.sub.2 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
aryl, substituted aryl, phenyl, substituted phenyl, heterocyclic
and substituted heterocyclic group selected from the group
consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl,
imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl and
benzothiazolyl; and R.sub.3 and R.sub.4 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
alkoxyl, substituted alkoxyl, phenyl, substituted phenyl, phenoxyl,
substituted phenoxyl, heterocyclic and substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl,
pyrrolyl, imidazoyl and thiazoyl.
2. The compound of general formula 1 as claimed in claim 1 selected
from the group consisting of compound of formula I and formula II,
##STR00221## wherein ##STR00222## is selected from the group
consisting of formula Ia, Ib and Ic; ##STR00223## is selected from
the group consisting of formula IIa, IIb and IIc; ##STR00224##
wherein, `G` is selected from the group consisting of H,
CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1; `Z` is selected from the
group consisting of O, S and NR.sub.2; `n` is any number from 0 to
2; `M` is selected from the group consisting of O, S, NR.sub.2 and
CR.sub.3R.sub.4; R, R.sub.1 and R.sub.2 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
aryl, substituted aryl, phenyl, substituted phenyl, heterocyclic
and substituted heterocyclic group selected from the group
consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl,
imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl and
benzothiazolyl; and R.sub.3 and R.sub.4 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
alkoxyl, substituted alkoxyl, phenyl, substituted phenyl, phenoxyl,
substituted phenoxyl, heterocyclic and substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl,
pyrrolyl, imidazoyl and thiazoyl.
3. The compound of general formula 1 as claimed in claim 1, wherein
compound of formula I is selected from the group consisting of
compound of formula IA, IB and IC, ##STR00225## wherein `X` is
CH.sub.2 or a direct bond; `Y` is selected from the group
consisting of O, S, and NR.sub.I2, or a direct bond; R.sub.II is
selected from the group consisting of H, alkyl, aryl, substituted
alkyl, substituted aryl, heterocyclic, substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl; and
substituted aryl is selected from the group consisting of F, Cl,
Br, I, NR.sub.I3R.sub.I4, CF.sub.3, OCF.sub.3, OR.sub.I5, NO.sub.2,
CHR.sub.I6R.sub.I7, alkyl group having C1 to C14, COOR.sub.I8, CHO,
and COR.sub.I9; R.sub.I2, R.sub.I3, R.sub.I4, R.sub.I5, R.sub.I8
and R.sub.I9 are each independently selected from the group
consisting of H, alkyl, alkoxyl, substituted alkoxyl, phenyl,
substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclic
and substituted heterocyclic group selected from the group
consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl, imidazoyl and
thiazoyl; and R.sub.I6 and R.sub.I7 are each independently selected
from the group consisting of H, alkyl, phenyl, substituted phenyl,
heterocyclic and substituted heterocyclic group selected from the
group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl, imidazoyl and
thiazoyl.
4. The compound of general formula 1 as claimed in claim 1, wherein
the compound of formula II is selected from the group consisting of
compound of formula IIA, IIB and IIC, ##STR00226## wherein `Z` is
selected from the group consisting of O, S, and NR.sub.II4; `n` is
any number from 0 to 2; `M` is selected from the group consisting
O, S, CH and N; R.sub.II1, R.sub.II2, R.sub.II3 and R.sub.II4 are
each independently selected from the group consisting of H, alkyl,
aryl, substituted alkyl, substituted aryl, heterocyclic and
substituted heterocyclic group selected from the group consisting
of pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl,
oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl,
thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and
benzothiazolyl; and substituted aryl is selected from the group
consisting of F, Cl, Br, I, NR.sub.II5R.sub.II6, CF.sub.3,
OCF.sub.3, OR.sub.II7, NO.sub.2, CHR.sub.II8R.sub.II9, alkyl group
having C1 to C14, COOR.sub.II10, CHO, and COR.sub.II11; R.sub.II5,
R.sub.II6, R.sub.II7, R.sub.II10 and R.sub.II11 are each
independently selected from the group consisting of H, alkyl
phenyl, substituted phenyl, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
thiophenyl, pyrrolyl, imidazoyl and thiazoyl; and R.sub.II8 and
R.sub.II9 are each independently selected from the group consisting
of H, alkyl alkoxy, substituted alkoxy, phenyl, substituted phenyl,
phenoxy, substituted phenoxy, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
thiophenyl, pyrrolyl, imidazoyl and thiazoyl.
5. The compound of general formula 1 as claimed in claim 1 selected
from the group consisting of:
(R)-2-{4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)methyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IA1),
(R)-2-{4-[4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA2),
(R)-2-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA3),
(R)-2-{4-[4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA4),
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA5),
(R)-2-{4-[4-(2-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA6),
(R)-2-{4-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA7),
(R)-2-{4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA8),
(R)-2-{4-[4-(4-isopropylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA9),
(R)-2-{4-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA10),
(R)-2-{4-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA11),
(R)-2-{4-[4-(3-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound
IA12),
(R)-2-{4-[4-(3-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA13),
(R)-2-{4-[4-(4-pyridin-2-yl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA14),
(R)-2-{4-[4-pentyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA15),
(R)-2-{4-[4-heptyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA16),
(R)-2-{3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA17),
(R)-2-{3-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA18),
(R)-2-{3-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA19),
(R)-2-{3-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA20),
(R)-2-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA21),
(R)-2-{2-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA22),
(R)-2-{2-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA23),
(R)-2-{2-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA24),
(R)-2-{4-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA25),
(R)-2-{4-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA26),
(R)-2-{4-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA27),
(R)-2-{4-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA28),
(R)-2-{4-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA29),
(R)-2-{4-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA30),
(R)-2-{4-[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA31),
(R)-2-{4-[4-(4-sec-butylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA32),
(R)-2-{3-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA33),
(R)-2-{3-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA34),
(R)-2-{3-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA35),
(R)-2-{3-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA36),
(R)-2-{3-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA37),
(R)-2-{3-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA38),
(R)-2-{2-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA39),
(R)-2-{2-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA40),
(R)-2-{2-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA41),
(R)-2-{2-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxy-
methyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA42),
(R)-2-{4-[5-phenyl-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-
-nitroimidazo[2,1-b]oxazole (compound IB1),
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB2),
(R)-2-{4-[5-(4-methylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB3),
(R)-2-{4-[5-(4-fluorophenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB4),
(R)-2-{4-[5-(4-trifluoromethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB5),
(R)-2-{4-[5-(4-ethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-
-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB6),
(R)-2-{4-[5-(4-fluorophenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB7),
(R)-2-{4-[5-(4-trifluoromethylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB8),
(R)-2-{4-[5-(4-methylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB9),
(R)-2-{4-[5-(4-trifluoromethoxyphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB10),
(R)-2-{4-[5-phenylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC1),
(R)-2-{4-[5-(4-ethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC2),
(R)-2-{4-[5-(2,4-difluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC3),
(R)-2-{4-[5-(2-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC4),
(R)-2-{4-[5-(4-trifluoromethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC5),
(R)-2-{4-[5-(4-methylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC6),
(R)-2-{4-[5-(4-methoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IC7),
(R)-2-{4-[5-(3-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC8),
(R)-2-{4-[5-(pyridin-2-yl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IC9),
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC10),
(R)-2-{4-[5-pentylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC11),
(R)-2-{4-[5-heptylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC12),
(R)-2-{4-[5-(4-trifluoromethoxyphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC13),
(R)-2-{4-[5-(4-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC14),
(R)-2-{4-[5-(4-trifluoromethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC15),
(R)-2-{4-[5-(2-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC16 5),
(R)-2-{4-[5-(4-methylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC17),
(R)-2-{4-[5-(4-isopropylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC18),
(R)-2-{4-[5-(4-ethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC19),
(R)-2-{4-[5-(4-sec-butylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC20),
(R)-2-{4-[5-(phenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC21),
(R)-2-{4-[5-(2,4-difluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC22),
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA1),
(R)-1-(4-ethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}urea(compound IIA2),
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA3),
(R)-1-(4-methylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA4),
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}urea(compound IIA5),
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA6),
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}thiourea(compound IIA7),
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA8),
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}thiourea(compound IIA9),
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA10),
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-tolyl)benzenesulfonamide(compound IIB1),
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethoxyphenyl)benzenesulfonamide(compound IIB2),
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethylphenyl)benzenesulfonamide(compound IIB3),
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-phenylbenzenesulfonamide(compound IIB4),
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-(p-tolyl)benzenesulfonamide(compound IIB5),
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-(p-trifluoromethylphenyl)benzenesulfonamide(compound
IIB6),
(R)-2-{4-(4-phenylpiperazin-1-yl)sulfonylphenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IIC1),
(R)-2-{4-[4-(4-fluorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC2),
(R)-2-{4-[4-(3-chlorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC3),
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]sulfonylphenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IIC4),
(R)-ethyl-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2yl)met-
hoxyphenyl] sulfonyl}piperazine-1-carboxylate(compound IIC5),
(R)-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2yl)methoxyph-
enyl] sulfonyl}piperazine-1-yl(phenyl)methanone(compound IIC6),
(R)-2-{4-(piperidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-ni-
troimidazo[2,1-b]oxazole (compound IIC7),
(R)-2-{4-[(4-phenylpiperidin-1-yl)sulfonyl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IIC8),
(R)-2-{4-(pyrrolidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-n-
itroimidazo[2,1-b]oxazole (compound IIC9), and
(R)-2-{4-(morpholinsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroim-
idazo[2,1-b]oxazole (compound IIC10).
6. The compound of general formula 1 as claimed in claim 1 for use
in treatment of tuberculosis.
7. The compound of general formula 1 as claimed in claim 1, wherein
said compound exhibits an in vitro anti-tuberculosis activity
against H37Rv Mycobacterium tuberculosis, MDR (resistant to
isoniazid and rifampicin) with MIC values in the range of 0.06 to
32 .mu.g/ml.
8. The compound of general formula 1 as claimed in claim 1 wherein
said compound exhibits an in vitro anti-tuberculosis activity
against XDR Mycobacterium tuberculosis (resistant to isoniazid,
rifampicin, amikacin and moxifloxacin) with MIC values in the range
of 0.12 to 32 .mu.g/ml.
9. The compound of general formula 1 as claimed in claim 1, wherein
said compound does not exhibit any cytotoxicity up to 40 .mu.g/ml
in macrophage J774 cells line and exhibits safety index more than
10.
10. The compound of general formula 1 as claimed in claim 1,
wherein said compound shows promising pharmacokinetic properties in
mouse model with C.sub.max of 1 to 5 .mu.g/ml and AUC.sub.0-24 of
10 to 50 .mu.g*hr/ml at oral dose of 5 mg/kg.
11. A process for the preparation of the compound of general
formula 1 as claimed in claim 1, said process comprising the steps:
reacting an epoxide (compound 9) ##STR00227## with a substituted
phenol selected from the group consisting of compounds of formula
13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f),
36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j)
##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232##
##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237##
##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242##
##STR00243## ##STR00244## ##STR00245## in an organic solvent
selected from the group consisting of N,N-dimethylformamide, DCM,
acetonitrile, THF and acetone in the presence of a base selected
from the group consisting of sodium hydride, cesium carbonate,
potassium carbonate and potassium bicarbonate at a temperature in
the range of -20.degree. C. to 10.degree. C. and stirring for a
period ranging between 1 to 24 hrs at a temperature in the range of
50.degree. C. to 80.degree. C. to obtain a compound of general
formula 1.
12. The compounds of general formula 1 as claimed in claim 1,
wherein the pharmaceutically acceptable salts are salts of an acid
selected from the group consisting of hydrochloric acid, sulphuric
acid, phosphoric acid, acetic acid, citric acid, oxalic acid,
malonic acid, salicylic acid, malic acid, fumaric acid, succinic
acid, ascorbic acid, maleic acid, methanesulfonic acid and
isoethonic acids or salts of a base selected from the group
consisting of potassium carbonate, sodium hydroxide, potassium
hydroxide, ammonia, triethylamine and triethanolamine.
13. A pharmaceutical composition for the treatment of tuberculosis,
wherein said composition comprises an effective amount of a
compound of general formula 1 as claimed in claim 1 or a
combination of a compound of general formula 1 as claimed in claim
1 and an anti-tubercular drug, optionally along with
pharmaceutically acceptable diluents excipients or carriers.
14. The pharmaceutical composition as claimed in claim 13, wherein
the ratio of compound of general formula 1 and an anti-tubercular
drug is in the range of 0.1% to 50% by weight.
15. The pharmaceutical composition as claimed in claim 13, wherein
said anti-tubercular drug is selected from the group consisting of
ethambutal, INH, rifampicin, pyrazinamide, streptomycin,
capreomycin, viomycin, enviomycin, kanamycin, amikacin,
ethionamide, prothionamide, p-amino salicylic acid, closerine,
ciprofloxacin, levoflaxacin and moxiflaxacin.
16. A method of treating tuberculosis comprising administering to a
subject in need of such treatment, an effective amount of a
compound of general formula 1 as claimed in claim 1 or a
combination of a compound of general formula 1 as claimed in claim
1 and an anti-tubercular drug, optionally along with
pharmaceutically acceptable diluents excipients or carriers.
17. The method as claimed in claim 16, wherein said subject is a
human.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the compounds of
6-nitro-2,3-dihydronitroimidazooxazoles scaffolds that have been
designed, synthesized and their biological evaluation result for
anti-tuberculosis are presented. The field of invention relates to
novel compounds of general formula 1, their method of preparations,
and their use as drugs for treatment of tuberculosis either alone
or in combination with other anti-tubercular treatments.
BACKGROUND OF THE INVENTION
[0002] Tuberculosis remains a leading infectious cause of death
worldwide and infects about one-third of the world's population.
The existing TB treatment needs a cocktail of three or four
different drugs (first-line drug regimen such as isoniazide,
pyrazinamide, and rifampin and several second line drug regimen
including ethionamide, para-aminosalicylic acid, kanamycin,
amikacin, capreomycin, ciprofloxacin, streptomycin, etc.) and is
exceedingly lengthy therapy which has lead to the emergence of
multidrug resistant TB (MDR-TB) and extensively drug resistant TB
(XDR-TB), which has further complicated the world situation
[BemerMelchior, P.; Bryskier, A.; Drugeon, H. B. J. Antimicrob.
Chemother. 2000, 46, 571; Abubaker, J.; Schraufnagel, D. J. Am.
Med. Assoc. 2000, 283, 54; Dye. C.; Scheele, S.; Dolin, P.;
Pathania, V.; Raviglione, M. C. J. Am. Med. Assoc. 1999, 282, 677].
The World Health Organization (WHO) has estimated that if the
present conditions remain unchanged, more than 30 million lives
will be claimed by TB between 2000 and 2020. TB has also been
declared as a global health emergency because of the increase in
secondary infections and/or coinfection in cancer and
immunocompromised patients (such as those infected with human
immunodeficiency virus). Therefore, the current situation
necessitates the development of new and potent anti-tuberculosis
agents with low toxicity profiles which are effective against both
drug-susceptible and drug-resistant strains of M. tuberculosis
along with being capable of shortening the current duration of
therapy and can be used in conjunction with drugs used for
treatment of secondary infections such as cancer and HIV. After
four decades, US-FDA recently approved TMC-207 {bedaquiline, a
diarylquinone derivative developed by Johnson & Johnson
(J&J)}, first drug against MDR-TB which works by inhibiting
ATP-synthase and approval of TMC-207 is being seen as a starting
point for a new era of TB treatment [Edney, Anna (Dec. 31, 2012).
"J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB".
Bloomberg. Retrieved 2013-01-01].
[0003] In the last decade, nitroimidazole skelton (A, FIG. 1)
developed great interest among the researchers of academic and
industrial fields, which lead to the discovery of two anti-TB
clinical candidates namely PA-824 (B, FIG. 1), a nitroimidazopyran
derivative, developed by PathoGenesis Corporation [US2006087358A
(2000); Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman,
D. R.; Arain, T. M.; Michael H. Langhorne, M. H.; Anderson, S. W.;
Towell, J. A.; Ying Yuan, Y.; McMurray, D. N.; Kreiswirth, B. N.;
Barryk, C. E.; Baker, W. R. Nature 2000, 405, 962] and OPC-67683
(C, FIG. 1), a 6-nitro-2,3-dihydronitroimidazooxazole derivative,
developed by Otsuka Pharmaceuticals Co. Ltd. [WO2004033463A1
(2004), EP1555267A1 (2005), WO2007013477A1 (2007); Sasaki, H.;
Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige,
T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med.
Chem. 2006, 49, 7854]. Initially, researchers at Ciba-Geigy India
started a programmne on the nitroimidazole skeleton (A, FIG. 1) to
discover novel anti-tuberculosis agent and in 1989 reported a
bicyclic nitroimidazooxazole (CGI 17341, D, FIG. 1) which possessed
potent in vitro activity and in vivo ant-TB activity [Nagarajan,
K.; Shankar, R. G.; Rajappa, S.; Shenoy, S. J.; Costa-Pereira, R.
Eur. J. Med. Chem. 1989, 24, 631] but later discontinued due to
mutagenic property [Ashtekar, D. R.; Costa-Perira, R.; Nagrajan,
K.; Vishvanathan, N.; Bhatt, A. D.; Rittel, W. Antimicrob. Agents
Chemother. 1993, 37, 183].
[0004] In present invention, new generation anti-TB molecules based
on 6-nitro-2,3-dihydronitroimidazooxazoles as inherent component
with triazoles, tetrazoles, isoxazoles, urea and sulphonamide
functionalities are designed that may fulfill the challenges of
anti-tuberculosis drug discovery such as good stability under
various conditions, high oral bioavailability, good elimination
half-life, free from genotoxicity/mutagenicity and hERG liabilities
and absence of drug-drug interactions which is critical in
combination treatments.
OBJECTIVE OF THE INVENTION
[0005] The main object of the present invention is to provide newer
generation triazoles, tetrazoles, isoxazoles, urea and sulphonamide
functionalities containing 6-nitro-2,3-dihydronitroimidazooxazoles
agents for treatment of tuberculosis.
[0006] Still another object of the present invention is to provide
a process for the preparation of triazoles, tetrazoles, isoxazoles,
urea and sulphonamide functionalities containing
6-nitro-2,3-dihydronitroimidazooxazoles.
[0007] Yet another object of the present invention is to provide
the combination therapy for the treatment of tuberculosis.
[0008] Still another object of the present invention is to provide
treatment against mult-drug resistant (MDR) and extensive drug
resistant (XDR) tuberculosis.
SUMMARY OF THE INVENTION
[0009] Accordingly the present invention relates to a compound of
general formula 1 or pharmaceutically acceptable salts thereof
##STR00002##
wherein [0010] `S` is selected from the group consisting of formula
Ia, Ib, Ic, IIa, IIb and IIc;
##STR00003##
[0010] wherein, [0011] `G` is selected from the group consisting of
H, CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1; [0012] `Z` is selected
from the group consisting of O, S and NR.sub.2; [0013] `n` is any
number from 0 to 2; [0014] `M` is selected from the group
consisting of O, S, NR.sub.2 and CR.sub.3R.sub.4; [0015] R,
R.sub.1, and R.sub.2 are each independently selected from the group
consisting of H, alkyl, substituted alkyl, aryl, substituted aryl,
phenyl, substituted phenyl, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl; [0016]
R.sub.3 and R.sub.4 are each independently selected from the group
consisting of H, alkyl, substituted alkyl, alkoxyl, substituted
alkoxyl, phenyl, substituted phenyl, phenoxyl, substituted
phenoxyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl,
imidazoyl and thiazoyl.
[0017] In an embodiment of the present invention, the compound of
general formula 1 is selected from the group consisting of compound
of formula I and formula II;
##STR00004##
wherein
##STR00005## [0018] is selected from the group consisting of
formula Ia, Ib and Ic;
##STR00006##
[0018] is selected from the group consisting of formula IIa, IIb
and IIc;
##STR00007##
wherein, [0019] `G` is selected from the group consisting of H,
CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1; [0020] `Z` is selected from
the group consisting of O, S and NR.sub.2; [0021] `n` is any number
from 0 to 2; [0022] `M` is selected from the group consisting of O,
S, NR.sub.2, and CR.sub.3R.sub.4; [0023] R, R.sub.1 and R.sub.2 are
each independently selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, phenyl, substituted
phenyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl,
thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl,
isoquinolinyl, benzooxazolyl, and benzothiazolyl; [0024] R.sub.3
and R.sub.4 are each independently selected from the group
consisting of H, alkyl, substituted alkyl, alkoxyl, substituted
alkoxyl, phenyl, substituted phenyl, phenoxyl, substituted
phenoxyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl,
imidazoyl and thiazoyl.
[0025] In still another embodiment of the present invention, the
compound of formula I is selected from the group consisting of
formula IA, IB and IC,
##STR00008##
wherein [0026] `X` is CH.sub.2 or a direct bond; [0027] `Y` is
selected from the group consisting of O, S, and NR.sub.I2, or a
direct bond; [0028] R.sub.II is selected from the group consisting
of H, alkyl, aryl, substituted alkyl, substituted aryl,
heterocyclic, substituted hetercocyclic group selected from the
group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl,
imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and
benzothiazolyl; and substituted aryl is selected from the group
consisting of F, Cl, Br, I, NR.sub.I3R.sub.I4, CF.sub.3, OCF.sub.3,
OR.sub.I5, NO.sub.2, CHR.sub.I6R.sub.I7, alkyl group having C1 to
C14, COOR.sub.I8, CHO, and COR.sub.I9; [0029] R.sub.I2, R.sub.I3,
R.sub.I4, R.sub.I5, R.sub.I8 and R.sub.I9 are each independently
selected from the group consisting of H, alkyl, alkoxyl,
substituted alkoxyl, phenyl, substituted phenyl, phenoxyl,
substituted phenoxyl, heterocyclic and substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl,
pyrrolyl, imidazoyl and thiazoyl; [0030] R.sub.I6 and R.sub.I7 are
each independently selected from the group consisting of H, alkyl,
phenyl, substituted phenyl, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
thiophenyl, pyrrolyl, imidazoyl and thiazoyl.
[0031] In yet another embodiment of the present invention, the
compound of formula II is selected from the group consisting of
compound of formula IIA, IIB and IIC,
##STR00009##
wherein [0032] `Z` is selected from the group consisting of O, S
and NR.sub.II4; [0033] `n` is any number from 0 to 2; [0034] `M` is
selected from the group consisting O, S, CH and N; [0035]
R.sub.II1, R.sub.II2, R.sub.II and R.sub.II4 are each independently
selected from the group consisting of H, alkyl, aryl, substituted
alkyl, substituted aryl, heterocyclic and substituted hetercocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl; and
substituted aryl is selected from the group consisting of F, Cl,
Br, I, NR.sub.II5R.sub.II6, CF.sub.3, OCF.sub.3, OR.sub.II7,
NO.sub.2, CHR.sub.II8R.sub.II9, alkyl group having C1 to C14,
COOR.sub.II10, CHO, and COR.sub.II11;
[0036] R.sub.II5, R.sub.II6, R.sub.II7, R.sub.II10 and R.sub.II11
are each independently selected from the group consisting of H,
alkyl, phenyl, substituted phenyl, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
thiophenyl, pyrrolyl, imidazoyl and thiazoyl;
[0037] R.sub.II8 and R.sub.II9 are each independently selected from
the group consisting of H, alkyl, alkoxy, substituted alkoxy,
phenyl, substituted phenyl, phenoxy, substituted phenoxy,
heterocyclic and substituted heterocyclic group selected from the
group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl, imidazoyl and
thiazoyl.
[0038] In still another embodiment of the present invention, the
compounds of general formula 1 are selected from the group
consisting of: [0039]
(R)-2-{4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)methyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IA1), [0040]
(R)-2-{4-[4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA2), [0041]
(R)-2-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA3), [0042]
(R)-2-{4-[4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA4), [0043]
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA5), [0044]
(R)-2-{4-[4-(2-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA6), [0045]
(R)-2-{4-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA7), [0046]
(R)-2-{4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA8),
[0047]
(R)-2-{4-[4-(4-isopropylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA9),
[0048]
(R)-2-{4-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA10), [0049]
(R)-2-{4-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA11), [0050]
(R)-2-{4-[4-(3-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound
IA12), [0051]
(R)-2-{4-[4-(3-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA13), [0052]
(R)-2-{4-[4-(4-pyridin-2-yl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA14), [0053]
(R)-2-{4-[4-pentyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA15), [0054]
(R)-2-{4-[4-heptyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA16), [0055]
(R)-2-{3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA17), [0056]
(R)-2-{3-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA18), [0057]
(R)-2-{3-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA19), [0058]
(R)-2-{3-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA20),
[0059]
(R)-2-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA21), [0060]
(R)-2-{2-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA22), [0061]
(R)-2-{2-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA23), [0062]
(R)-2-{2-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA24),
[0063]
(R)-2-{4-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA25), [0064]
(R)-2-{4-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA26),
[0065]
(R)-2-{4-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA27), [0066]
(R)-2-{4-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA28),
[0067]
(R)-2-{4-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA29),
[0068]
(R)-2-{4-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA30), [0069]
(R)-2-{4-[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxym-
ethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA31), [0070]
(R)-2-{4-[4-(4-sec-butylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA32), [0071]
(R)-2-{3-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA33), [0072]
(R)-2-{3-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA34),
[0073]
(R)-2-{3-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA35), [0074]
(R)-2-{3-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA36),
[0075]
(R)-2-{3-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA37),
[0076]
(R)-2-{3-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA38), [0077]
(R)-2-{2-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1--
yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA39), [0078]
(R)-2-{2-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA40),
[0079]
(R)-2-{2-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA41), [0080]
(R)-2-{2-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA42),
[0081]
(R)-2-{4-[5-phenyl-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-
-nitroimidazo[2,1-b]oxazole (compound IB1), [0082]
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB2),
[0083]
(R)-2-{4-[5-(4-methylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB3), [0084]
(R)-2-{4-[5-(4-fluorophenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB4), [0085]
(R)-2-{4-[5-(4-trifluoromethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB5),
[0086]
(R)-2-{4-[5-(4-ethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-
-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB6), [0087]
(R)-2-{4-[5-(4-fluorophenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB7), [0088]
(R)-2-{4-[5-(4-trifluoromethylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB8),
[0089]
(R)-2-{4-[5-(4-methylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB9), [0090]
(R)-2-{4-[5-(4-trifluoromethoxyphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB10),
[0091]
(R)-2-{4-[5-phenylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC1), [0092]
(R)-2-{4-[5-(4-ethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC2), [0093]
(R)-2-{4-[5-(2,4-difluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC3), [0094]
(R)-2-{4-[5-(2-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC4), [0095]
(R)-2-{4-[5-(4-trifluoromethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC5), [0096]
(R)-2-{4-[5-(4-methylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC6), [0097]
(R)-2-{4-[5-(4-methoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IC7), [0098]
(R)-2-{4-[5-(3-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC8), [0099]
(R)-2-{4-[5-(pyridin-2-yl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IC9), [0100]
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC10), [0101]
(R)-2-{4-[5-pentylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC11), [0102]
(R)-2-{4-[5-heptylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC12), [0103]
(R)-2-{4-[5-(4-trifluoromethoxyphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC13),
[0104]
(R)-2-{4-[5-(4-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC14), [0105]
(R)-2-{4-[5-(4-trifluoromethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC15),
[0106]
(R)-2-{4-[5-(2-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC16), [0107]
(R)-2-{4-[5-(4-methylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC17), [0108]
(R)-2-{4-[5-(4-isopropylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC18), [0109]
(R)-2-{4-[5-(4-ethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC19), [0110]
(R)-2-{4-[5-(4-sec-butylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC20), [0111]
(R)-2-{4-[5-(phenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC21), [0112]
(R)-2-{4-[5-(2,4-difluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC22),
[0113]
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA1), [0114]
(R)-1-(4-ethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}urea(compound IIA2), [0115]
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA3), [0116]
(R)-1-(4-methylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA4), [0117]
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}urea(compound IIA5), [0118]
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA6), [0119]
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}thiourea(compound IIA7), [0120]
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA8), [0121]
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}thiourea(compound IIA9), [0122]
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA10), [0123]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-tolyl)benzenesulfonamide(compound IIB1), [0124]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethoxyphenyl)benzenesulfonamide(compound IIB2), [0125]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethylphenyl)benzenesulfonamide(compound IIB3), [0126]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-phenylbenzenesulfonamide(compound IIB4), [0127]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-(p-tolyl)benzenesulfonamide(compound IIB5), [0128]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-(p-trifluoromethylphenyl)benzenesulfonamide(compound
IIB6), [0129]
(R)-2-{4-(4-phenylpiperazin-1-yl)sulfonylphenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC1), [0130]
(R)-2-{4-[4-(4-fluorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC2), [0131]
(R)-2-{4-[4-(3-chlorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC3), [0132]
(R)-2-{4-[4-(4-trifluoromethoxyphenyppiperazin-1-yl]sulfonylphenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IIC4), [0133]
(R)-ethyl-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol--
2yl)methoxyphenyl] sulfonyl}piperazine-1-carboxylate (compound
IIC5), [0134]
(R)-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2yl)me-
thoxyphenyl] sulfonyl}piperazine-1-yl(phenyl)methanone (compound
IIC6), [0135]
(R)-2-{4-(piperidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IIC7), [0136]
(R)-2-{4-[(4-phenylpiperidin-1-yl)sulfonyl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IIC8), [0137]
(R)-2-{4-(pyrrolidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-n-
itroimidazo[2,1-b]oxazole (compound IIC9) and [0138]
(R)-2-{4-(morpholinsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroim-
idazo[2,1-b]oxazole (compound IIC10)
[0139] In yet another embodiment of the present invention, the
compound of general formula 1 is useful in treatment of
tuberculosis.
[0140] In still another embodiment of the present invention, the
compound of general formula 1 exhibits an in vitro
anti-tuberculosis activity against H37Rv Mycobacterium
tuberculosis, MDR (resistant to isoniazid and rifampicin) with MIC
values in the range of 0.06 to 32 .mu.g/ml.
[0141] In yet another embodiment of present invention, the compound
of general formula 1 exhibits an in vitro anti-tuberculosis
activity against XDR Mycobacterium tuberculosis (resistant to
isoniazid, rifampicin, amikacin and moxifloxacin) with MIC values
in the range of 0.12 to 32 .mu.g/ml.
[0142] In still another embodiment of the present invention, the
compound of general formula 1 does not exhibit any cytotoxicity up
to 40 .mu.g/ml in macrophage J774 cells line and exhibits safety
index more than 10.
[0143] In yet another embodiment of the present invention, the
compound of general formula 1 shows promising pharmacokinetic
properties in mouse model with C.sub.max of 1 to 5 .mu.g/ml and
AUC.sub.0-24 of 10 to 50 .mu.g hr/ml at oral dose of 5 mg/kg.
[0144] In still another embodiment of the present invention, the
compound of general formula 1 exhibits synergistic and additive
effect with known anti-tubercular drugs in combination studies.
[0145] An embodiment of the present invention provides a process
for the preparation of a compound of general formula 1 comprising
the steps:
[0146] reacting an epoxide (compound 9)
##STR00010##
with a substituted phenol selected from the group consisting of
compounds of formula 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f),
25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and
53(a-j) in an organic solvent selected from the group consisting of
N,N-dimethylformamide, DCM, acetonitrile, THF and acetone in
presence of a base selected from the group consisting of sodium
hydride, cesium carbonate, potassium carbonate and potassium
bicarbonate at a temperature in the range of -20.degree. C. to
10.degree. C. and stirring for a period ranging between 1 to 24 hrs
at a temperature in the range of 50.degree. C. to 80.degree. C. to
obtain the compound of general formula 1.
[0147] In yet another embodiment of the present invention, the
pharmaceutically acceptable salts are salts of an acid selected
from the group consisting of hydrochloric acid, sulfuric acid,
phosphoric acid, acetic acid, citric acid, oxalic acid, malonic
acid, salicylic acid, malic acid, fumaric acid, succinic acid,
ascorbic acid, maleic acid, methanesulfonic acid and isoethonic
acid and salts of a base selected from the group consisting of
potassium carbonate, sodium hydroxide, potassium hydroxide,
ammonia, triethylamine and triethanolamine.
[0148] In still another embodiment of the present invention, the
process for the preparation of the salt of compound of general
formula 1 comprising the steps: [0149] mixing a compound of general
formula 1 with an acid or a base in the ratio of 1:1 by weight
wherein, said acid is selected from the group consisting of
hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid,
citric acid, oxalic acid, malonic acid, salicylic acid, malic acid,
fumaric acid, succinic acid, ascorbic acid, maleic acid and
methanesulfonic acid and said base is selected from the group
consisting of sodium hydroxide, potassium hydroxide and ammonium
hydroxide, in water to obtain a reaction mixture; [0150] stirring
said reaction mixture for 1-2 hrs followed by evaporating water to
obtain the salt of compound of formula 1.
[0151] An embodiment of the present invention provides a
pharmaceutical composition for treatment of tuberculosis comprising
an effective amount of a compound of general formula 1 or a
combination of a compound of general formula 1 and an
anti-tubercular drug, optionally along with pharmaceutically
acceptable diluents, excipients or carriers.
[0152] In still another embodiment of the present invention, the
ratio of compound of formula 1 and an anti-tubercular drug in the
pharmaceutical composition is in the range of 0.1% to 50% by
weight.
[0153] In yet another embodiment of the present invention, the
anti-tubercular drug used in the pharmaceutical composition is
selected from the group consisting of ethambutal, INH, rifampicin,
pyrazinamide, streptomycin, capreomycin, viomycin, enviomycin,
kanamycin, amikacin, ethionamide, prothionamide, p-amino salicylic
acid, closerine, ciprofloxacin, levoflaxacin and moxiflaxacin.
[0154] An embodiment of the present invention provides a method of
treating tuberculosis comprising administering to a subject, an
effective amount of a compound of general formula 1 or a
combination of a compound of general formula 1 and an
anti-tubercular drug, optionally along with pharmaceutically
acceptable diluents, excipients or carriers.
[0155] In an embodiment of the present invention, there is provided
a method for treating tuberculosis, wherein the subject is a
human.
[0156] In another embodiment of the present invention, there is
provided a method for treating tuberculosis, wherein the
anti-tubercular drug used in combination with the compound of
formula 1 is selected from the group consisting of ethambutal, INH,
rifampicin, pyrazinamide, streptomycin, capreomycin, viomycin,
enviomycin, kanamycin, amikacin, ethionamide, prothionamide,
p-amino salicylic acid, closerine, ciprofloxacin, levoflaxacin and
moxiflaxacin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0157] FIG. 1 shows the structure of anti-TB clinical
candidates.
[0158] FIG. 2 shows the general structure of representative of
compounds referred to in Table 1, 2, 3, 4, 5, 6, 7 and 8.
[0159] FIG. 3 shows the retro-synthetic approach for the synthesis
of compounds of formula I and II of general formula 1.
[0160] FIG. 4 shows the synthetic scheme (scheme 1) for the
synthesis of fragment A (compound 9).
[0161] FIG. 5 shows the synthetic scheme (scheme 2) for the
synthesis of fragment B [compounds 13(a-p)].
[0162] FIG. 6 shows the synthetic scheme (scheme 3) for the
synthesis of fragment B [compounds 16(a-d)].
[0163] FIG. 7 shows the synthetic scheme (scheme 4) for the
synthesis of fragment B [compounds 19(a-d)].
[0164] FIG. 8 shows the synthetic scheme (Scheme 5) for coupling of
A (compound 9) with B [compound 13(a-p), 16(a-d), 19(a-d)] to
generate the representing compounds of formula IA of general
formula 1.
[0165] FIG. 9 shows the synthetic scheme (scheme 6) for the
synthesis of fragment B [compounds 23(a-h)].
[0166] FIG. 10 shows the synthetic scheme (scheme 7) for the
synthesis of fragment B [compounds 24(a-f)].
[0167] FIG. 11 shows the synthetic scheme (scheme 8) for the
synthesis of fragment B [compounds 25(a-d)].
[0168] FIG. 12 shows the synthetic scheme (Scheme 9) for coupling
of A (compound 9) with B [compound 23(a-h), 24(a-f), 25(a-d)] to
generate the representing compounds of formula IA of general
formula 1.
[0169] FIG. 13 shows the synthetic scheme (scheme 10) for the
synthesis of fragment B [compounds 30(a-f)].
[0170] FIG. 14 shows the synthetic scheme (Scheme 11) for coupling
of A (compound 9) with B [compound 30(a-f)] to generate the
representing compounds of formula IB of general formula 1.
[0171] FIG. 15 shows the synthetic scheme (scheme 12) for the
synthesis of fragment B [compounds 36(a-d)].
[0172] FIG. 16 shows the synthetic scheme (Scheme 13) for coupling
of A (compound 9) with B [compound 36(a-d)] to generate the
representing compounds of formula IB of general formula 1.
[0173] FIG. 17 shows the synthetic scheme (scheme 14) for the
synthesis of fragment B [compounds 41(a-l)].
[0174] FIG. 18 shows the synthetic scheme (Scheme 15) for coupling
of A (compound 9) with B [compound 41(a-l)] to generate the
representing compounds of formula IC of general formula 1.
[0175] FIG. 19 shows the synthetic scheme (scheme 16) for the
synthesis of fragment C (compounds 42 a-j).
[0176] FIG. 20 shows the synthetic scheme (Scheme 17) for coupling
of A (compound 9) with B [compound 42(a-j)] to generate the
representing compounds of formula IC of general formula 1.
[0177] FIG. 21 shows the synthetic scheme (scheme 18) for the
synthesis of fragment C [compounds 45(a-j)].
[0178] FIG. 22 shows the synthetic scheme (Scheme 19) for coupling
of A (compound 9) with C [compound 45(a-j)] to generate the
representing compounds of formula IIA of general formula 1.
[0179] FIG. 23 shows the synthetic scheme (scheme 20) for the
synthesis of fragment C [compounds 49(a-f)].
[0180] FIG. 24 shows the synthetic scheme (Scheme 21) for coupling
of A (compound 9) with C [compound 49(a-f)] to generate the
representing compounds of formula IIB of general formula 1.
[0181] FIG. 25 shows the synthetic scheme (scheme 22) for the
synthesis of fragment C [compounds 53(a-j)].
[0182] FIG. 26 shows the synthetic scheme (Scheme 23) for coupling
of A (compound 9) with C [compound 53(a-j)] to generate the
representing compounds of formula IIC of general formula 1.
BRIEF DESCRIPTION OF THE TABLES
[0183] Table 1 shows the structure of representative compounds
IA1-IA16 belonging to formula IA and synthesized as per scheme 5
provided in FIG. 8.
[0184] Table 2 shows the structure of representative compounds
IA17-IA24 belonging to formula IA and synthesized as per scheme 5
provided in FIG. 8.
[0185] Table 3 shows the structure of representative compounds
IA25-IA42 belonging to formula IA and synthesized as per scheme 9
provided in FIG. 12.
[0186] Table 4 shows the structure of representative compounds
IB1-IB10 belonging to formula IB and synthesized as per scheme 11
and scheme 13 provided in FIG. 14 and FIG. 16, respectively.
[0187] Table 5 shows the structure of representative compounds
IC1-IC22 belonging to formula IC and synthesized as per scheme 15
and scheme 17 provided in FIG. 18 and FIG. 20, respectively.
[0188] Table 6 shows the structure of representative compounds
IIA1-IIA10 belonging to formula IIA and synthesized as per scheme
19 provided in FIG. 22.
[0189] Table 7 shows the structure of representative compounds
IIB1-IIB6 belonging to formula JIB and synthesized as per scheme 21
provided in FIG. 24.
[0190] Table 8 shows the structure of representative compounds
IIC1-IIC10 belonging to formula IIC and synthesized as per scheme
23 provided in FIG. 26.
[0191] Table 9 shows the physico-chemical properties,
anti-tuberculosis activity and cytotoxicity of representative
compound shown in tables 1 to 8.
[0192] Table 10 shows the combination studies results of OPC-67683
and selected compounds of general formula 1(IA25 and IIA3) with
rifampicine, INH and ethambutol against M. tuberculosis H37Rv.
[0193] Table 11 shows the In vivo pharmacokinetic properties of
OPC-67683, and selected compounds of general formula 1(IA25, IA33,
IC13 and IC14).
ABBREVIATION USED
[0194] H.R.: Heterocyclic Ring
DETAILED DESCRIPTION OF THE INVENTION
[0195] The present invention relates to new generation of
triazoles, tetrazoles, isoxazoles, urea and sulphonamide
functionalities containing 6-nitro-2,3-dihydronitroimidazooxazoles
agents, their method of preparation, and their use as drugs for
treatment of tuberculosis either alone or in combination with other
anti-tubercular agents.
[0196] The present invention describes a compound having a general
formula 1
##STR00011##
wherein [0197] substituent `S` is selected from the group
consisting of formula Ia, Ib, Ic, IIa, IIb and IIc;
[0197] ##STR00012## [0198] wherein, [0199] `G` is selected from the
group consisting of H, CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1;
[0200] `Z` is selected from the group consisting of O, S and
NR.sub.2; [0201] `n` is any number from 0 to 2; [0202] `M` is
selected from the group consisting of O, S, NR.sub.2 and
CR.sub.3R.sub.4; [0203] R, R.sub.1 and R.sub.2 are each
independently selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, phenyl, substituted
phenyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl,
thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl,
isoquinolinyl, benzooxazolyl and benzothiazolyl; [0204] R.sub.3 and
R.sub.4 are each independently selected from the group consisting
of H, alkyl, substituted alkyl, alkoxyl, substituted alkoxyl,
phenyl, substituted phenyl, phenoxyl, substituted phenoxyl,
heterocyclic and substituted heterocyclic group selected from the
group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl, imidazoyl and
thiazoyl.
[0205] The compound of general formula 1 is selected from the group
consisting of compound of formula I and formula II,
##STR00013##
wherein
##STR00014##
is selected from the group consisting of formula Ia, Ib and Ic;
##STR00015##
is selected from the group consisting of formula IIa, IIb and
IIc;
##STR00016##
wherein, [0206] `G` is selected from the group consisting of H,
CH.sub.2OR.sub.1, OR.sub.1 and R.sub.1; [0207] `Z` is selected from
the group consisting of O, S and NR.sub.2; [0208] `n` is any number
from 0 to 2; and [0209] `M` is selected from the group consisting
of O, S, NR.sub.2 and CR.sub.3R.sub.4; [0210] R, R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of H, alkyl, substituted alkyl, aryl, substituted aryl, phenyl,
substituted phenyl, heterocyclic and substituted heterocyclic group
selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl; [0211]
R.sub.3 and R.sub.4 are each independently selected from the group
consisting of H, alkyl, substituted alkyl, alkoxyl, substituted
alkoxyl, phenyl, substituted phenyl, phenoxyl, substituted
phenoxyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl,
imidazoyl and thiazoyl.
[0212] In another aspect of the present invention, a preferred
subclass of compound of general formula 1 is selected from the
group consisting of compound of formula IA, IB and IC;
##STR00017##
wherein [0213] `X` is CH.sub.2 or a direct bond; [0214] `Y` is
selected from the group consisting of O, S and NR.sub.I2, or a
direct bond; [0215] R.sub.II is selected from the group consisting
of H, alkyl, aryl, substituted alkyl, substituted aryl,
heterocyclic, substituted hetercocyclic group selected from the
group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl,
imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl and
benzothiazolyl; and substituted aryl is selected from the group
consisting of F, Cl, Br, I, NR.sub.I3R.sub.I4, CF.sub.3, OCF.sub.3,
OR.sub.I5, NO.sub.2, CHR.sub.I6R.sub.I7, alkyl group having C1 to
C14, COOR.sub.I8, CHO and COR.sub.I9; [0216] R.sub.I2, R.sub.I3,
R.sub.I4, R.sub.I5, R.sub.I8 and R.sub.I9 are each independently
selected from the group consisting of H, alkyl, alkoxyl,
substituted alkoxyl, phenyl, substituted phenyl, phenoxyl,
substituted phenoxyl, heterocyclic and substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl,
pyrrolyl, imidazoyl and thiazoyl; [0217] R.sub.I6 and R.sub.I7 are
each independently selected from the group consisting of H, alkyl,
phenyl, substituted phenyl, heterocyclic and substituted
heterocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
thiophenyl, pyrrolyl, imidazoyl and thiazoyl.
[0218] In another aspect of the present invention, another
preferred subclass of compound of general formula 1 is selected
from the group consisting of compound of formula IIA, IIB and
IIC;
##STR00018##
wherein [0219] `Z` is selected from the group consisting of O, S
and NR.sub.II4; [0220] `n` is any number from 0 to 2; and [0221]
`M` is selected from the group consisting of O, S, CH and N; [0222]
R.sub.II1, R.sub.II2, R.sub.II3 and R.sub.II4 are each
independently selected from the group consisting of H, alkyl, aryl,
substituted alkyl, substituted aryl, heterocyclic and substituted
hetercocyclic group selected from the group consisting of pyridyl,
triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl,
benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl,
quinolinyl, isoquinolinyl, benzooxazolyl and benzothiazolyl; and
substituted aryl is selected from the group consisting of F, Cl,
Br, I, NR.sub.II5R.sub.II6, CF.sub.3, OCF.sub.3, OR.sub.II7,
NO.sub.2, CHR.sub.II8R.sub.II9, alkyl group having C1 to C14,
COOR.sub.II10, CHO, and COR.sub.II11; [0223] R.sub.II5, R.sub.II6,
R.sub.II7, R.sub.II10 and R.sub.II11 are each independently
selected from the group consisting of H, alkyl, phenyl, substituted
phenyl, heterocyclic and substituted heterocyclic group selected
from the group consisting of pyridyl, triazolyl, triazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl, pyrrolyl,
imidazoyl and thiazoyl; [0224] R.sub.II8 and R.sub.II9 are each
independently selected from the group consisting of H, alkyl,
alkoxy, substituted alkoxy, phenyl, substituted phenyl, phenoxy,
substituted phenoxy, heterocyclic and substituted heterocyclic
group selected from the group consisting of pyridyl, triazolyl,
triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, thiophenyl,
pyrrolyl, imidazoyl and thiazoyl.
[0225] The compound of general formula 1 is useful in treatment of
tuberculosis.
[0226] The compound of general formula 1 exhibits potent minimum
inhibitory concentration (MIC) against H37Rv Mycobacterium
tuberculosis, MDR-TB (resistant to isoniazid and rifampicin) in the
range of 0.06 to 32 .mu.g/ml.
[0227] The compound of general formula 1 exhibits MIC against XDR
Mycobacterium tuberculosis (resistant to isoniazid, rifampicin,
amikacin and moxifloxacin) in the range of 0.12 to 32 .mu.g/ml.
[0228] The compound of general formula 1 does not exhibit any
cytotoxicity up to 40 .mu.g/ml in macrophage J774 cells line and
exhibits safety index more than 10.
[0229] The compound of general formula 1, wherein one of the
representing compound exhibits promising and better pharmacokinetic
properties in mouse model with C.sub.max of 1 to 5 .mu.g/ml and
AUC.sub.0-24 of 10 to 50 .mu.g*hr/ml at an oral dose of 5
mg/kg.
[0230] The compounds of general formula 1 exhibit synergistic and
additive effects with other known anti-tubercular drugs such as
rafamicin, isoniazid and ethambutol in combination studies.
[0231] The compound of formula IA of general formula 1 is prepared
by reacting an epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 13(a-p),
16(a-d), 19(a-d), 23(a-h), 24(a-f) and 25 (a-d) in an organic
solvent selected from the group consisting of
N,N-dimethylformamide, DCM, acetonitrile, THF and acetone in
presence of a base selected from the group consisting of cesium
carbonate, potassium carbonate, potassium bicarbonate and sodium
hydride at a temperature in the range of -20.degree. C. to
10.degree. C. and stirring for 1 to 24 hrs at a temperature in the
range of 50.degree. C. to 80.degree. C.
[0232] The compound of formula IB of general formula 1 is prepared
by reacting the epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 30(a-f)
and 36(a-d) in an organic solvent selected from the group
consisting of DCM, acetonitrile, THF, acetoneand N,
N-dimethylformamide in presence of a base selected from the group
consisting of cesium carbonate, potassium carbonate, potassium
bicarbonate and sodium hydride at a temperature in the range of
-20.degree. C. to 10.degree. C. and stirring for 1 to 24 hrs at a
temperature in the range of 50.degree. C. to 80.degree. C.
[0233] The compound of formula IC of general formula 1 is prepared
by reacting an epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 41(a-l)
and 42(a-j) in an organic solvent selected from the group
consisting of DCM, acetonitrile, THF, acetone and N,
N-dimethylformamide in presence of a base selected from the group
consisting of cesium carbonate, potassium carbonate, potassium
bicarbonate and sodium hydride at a temperature in the range of
-20.degree. C. to 10.degree. C. and stirring for 1 to 24 hrs at a
temperature in the range of 50.degree. C. to 80.degree. C.
[0234] The compound of formula IIA of general formula 1 is prepared
by reacting an epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 45(a-j)
in an organic solvent selected from the group consisting of DCM,
acetonitrile, THF, acetone and N,N-dimethylformamide in presence of
a base selected from the group consisting of cesium carbonate,
potassium carbonate, potassium bicarbonate and sodium hydride at a
temperature in the range of -20.degree. C. to 10.degree. C. and
stirring for 1 to 24 hrs at a temperature in the range of
50.degree. C. to 80.degree. C.
[0235] The compound of formula IIB of general formula 1 is prepared
by reacting an epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 49(a-f)
in an organic solvent selected from the group consisting of DCM,
acetonitrile, THF, acetone and N,N-dimethylformamide in presence of
a base selected from the group consisting of cesium carbonate,
potassium carbonate, potassium bicarbonate and sodium hydride at a
temperature in the range of -20.degree. C. to 10.degree. C. and
stirring for 1 to 24 hrs at a temperature in the range of
50.degree. C. to 80.degree. C.
[0236] The compound of formula IIC of general formula 1 is prepared
by reacting an epoxide (compound 9) with a substituted phenol
selected from the group consisting of compounds of formula 53(a-j)
in an organic solvent selected from the group consisting of DCM,
acetonitrile, THF, acetone and N,N-dimethylformamide in presence of
a base selected from the group consisting of cesium carbonate,
potassium carbonate, potassium bicarbonate and sodium hydride at a
temperature in the range of -20.degree. C. to 10.degree. C. and
stirring for 1 to 24 hrs at a temperature in the range of
50.degree. C. to 80.degree. C.
[0237] The compounds of the present invention, combination thereof,
isomers, and physiologically functionally salt derivatives are
useful for treatment of Mycobacterium tuberculosis infection.
[0238] In the present invention, the pharmaceutically acceptable
salts are salts of an acid selected from the group consisting of
hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid,
citric acid, oxalic acid, malonic acid, salicylic acid, malic acid,
fumaric acid, succinic acid, ascorbic acid, maleic acid,
methanesulfonic acid and isoethonic acid or salts of a base
selected from the group consisting of potassium carbonate, sodium
hydroxide, potassium hydroxide, ammonia, triethylamine and
triethanolamine.
[0239] The most preferred compounds of formula I and II of general
formula 1 are: [0240]
(R)-2-{4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)methyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IA1), [0241]
(R)-2-{4-[4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA2), [0242]
(R)-2-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA3), [0243]
(R)-2-{4-[4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA4), [0244]
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA5), [0245]
(R)-2-{4-[4-(2-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA6), [0246]
(R)-2-{4-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA7), [0247]
(R)-2-{4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA8),
[0248]
(R)-2-{4-[4-(4-isopropylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA9),
[0249]
(R)-2-{4-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA10), [0250]
(R)-2-{4-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA11), [0251]
(R)-2-{4-[4-(3-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound
IA12), [0252]
(R)-2-{4-[4-(3-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA13), [0253]
(R)-2-{4-[4-(4-pyridin-2-yl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA14), [0254]
(R)-2-{4-[4-pentyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA15), [0255]
(R)-2-{4-[4-heptyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA16), [0256]
(R)-2-{3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA17), [0257]
(R)-2-{3-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA18), [0258]
(R)-2-{3-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA19), [0259] (R)-2-{3-[4-(2,4-di
fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-
-nitroimidazo[2,1-b]oxazole (compound IA20), [0260]
(R)-2-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA21), [0261]
(R)-2-{2-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA22), [0262]
(R)-2-{2-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA23), [0263]
(R)-2-{2-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA24),
[0264]
(R)-2-{4-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA25), [0265]
(R)-2-{4-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA26),
[0266]
(R)-2-{4-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA27), [0267]
(R)-2-{4-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA28),
[0268]
(R)-2-{4-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA29),
[0269]
(R)-2-{4-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA30), [0270]
(R)-2-{4-[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxym-
ethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA31), [0271]
(R)-2-{4-[4-(4-sec-butylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA32), [0272]
(R)-2-{3-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phen-
oxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA33), [0273]
(R)-2-{3-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA34),
[0274]
(R)-2-{3-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA35), [0275]
(R)-2-{3-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA36),
[0276]
(R)-2-{3-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA37),
[0277]
(R)-2-{3-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymeth-
yl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA38), [0278]
(R)-2-{2-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1--
yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA39), [0279]
(R)-2-{2-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroirnidazo[2,1-b]oxazole (compound
IA40), [0280]
(R)-2-{2-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-y-
l]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA41), [0281]
(R)-2-{2-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA42),
[0282]
(R)-2-{4-[5-phenyl-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-
-nitroimidazo[2,1-b]oxazole (compound IB1), [0283]
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB2),
[0284]
(R)-2-{4-[5-(4-methylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB3), [0285]
(R)-2-{4-[5-(4-fluorophenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB4), [0286]
(R)-2-{4-[5-(4-trifluoromethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB5),
[0287]
(R)-2-{4-[5-(4-ethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-
-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB6), [0288]
(R)-2-{4-[5-(4-fluorophenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB7), [0289]
(R)-2-{4-[5-(4-trifluoromethylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB8),
[0290]
(R)-2-{4-[5-(4-methylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB9), [0291]
(R)-2-{4-[5-(4-trifluoromethoxyphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB10),
[0292]
(R)-2-{4-[5-phenylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC1), [0293]
(R)-2-{4-[5-(4-ethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC2), [0294]
(R)-2-{4-[5-(2,4-di
fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimi-
dazo[2,1-b]oxazole (compound IC3), [0295]
(R)-2-{4-[5-(2-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC4), [0296]
(R)-2-{4-[5-(4-trifluoromethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC5), [0297]
(R)-2-{4-[5-(4-methylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC6), [0298]
(R)-2-{4-[5-(4-methoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IC7), [0299]
(R)-2-{4-[5-(3-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IC8), [0300]
(R)-2-{4-[5-(pyridin-2-yl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IC9), [0301]
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC10), [0302]
(R)-2-{4-[5-pentylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC11), [0303]
(R)-2-{4-[5-heptylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IC12), [0304]
(R)-2-{4-[5-(4-trifluoromethoxyphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC13),
[0305]
(R)-2-{4-[5-(4-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC14), [0306]
(R)-2-{4-[5-(4-trifluoromethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC15),
[0307]
(R)-2-{4-[5-(2-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC16), [0308]
(R)-2-{4-[5-(4-methylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC17), [0309]
(R)-2-{4-[5-(4-isopropylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC18), [0310]
(R)-2-{4-[5-(4-ethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC19), [0311]
(R)-2-{4-[5-(4-sec-butylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC20), [0312]
(R)-2-{4-[5-(phenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IC21), [0313]
(R)-2-{4-[5-(2,4-difluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC22),
[0314]
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA1), [0315]
(R)-1-(4-ethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}urea(compound IIA2), [0316]
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA3), [0317]
(R)-1-(4-methylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA4), [0318]
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}urea(compound IIA5), [0319]
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA6), [0320]
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]o-
xazol-2-yl)methoxyphenyl}thiourea(compound IIA7), [0321]
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidaz-
o[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA8), [0322]
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}thiourea(compound IIA9), [0323]
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydro
imidazo[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA10),
[0324]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-tolyl)benzenesulfonamide(compound IIB1), [0325]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethoxyphenyl)benzenesulfonamide(compound IIB2), [0326]
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N--
(p-trifiuoromethylphenyl)benzenesulfonamide(compound IIB3), [0327]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-phenylbenzenesulfonamide(compound IIB4), [0328]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)m-
ethoxy}-N-(p-tolyl)benzenesulfonamide(compound IIB5), [0329]
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydro
imidazo[2,1-b]oxazol-2-yl)methoxy}-N-(p-trifluoromethylphenyl)benzenesulf-
onamide(compound IIB6), [0330]
(R)-2-{4-(4-phenylpiperazin-1-yl)sulfonylphenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IIC1), [0331]
(R)-2-{4-[4-(4-fluorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC2), [0332]
(R)-2-{4-[4-(3-chlorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC3), [0333]
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]sulfonylphenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IIC4), [0334]
(R)-ethyl-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol--
2yl)methoxyphenyl] sulfonyl}piperazine-1-carboxylate(compound
IIC5), [0335]
(R)-{4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2yl)me-
thoxyphenyl] sulfonyl}piperazine-1-yl(phenyl)methanone(compound
IIC6), [0336]
(R)-2-{4-(piperidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IIC7), [0337]
(R)-2-{4-[(4-phenylpiperidin-1-yl)sulfonyl]phenoxymethyl}-2,3-dihydro-2-m-
ethyl-6-nitroimidazo[2,1-b]oxazole (compound IIC8), [0338]
(R)-2-{4-(pyrrolidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-n-
itroimidazo[2,1-b]oxazole (compound IIC9) and [0339]
(R)-2-{4-(morpholinsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroim-
idazo[2,1-b]oxazole (compound IIC10)
EXAMPLES
Synthesis of Compounds
[0340] The following examples are given by way of illustrating the
present invention and should not be construed to limit the scope of
the invention:
Example 1
Synthesis of Fragment A, an Epoxide (Compound 9)
[0341] Fragment A (compound 9) was successfully synthesized from a
starting material 4-nitroimidiazole 1 as shown in scheme 1
(provided in FIG. 4) by following the known procedure (Sasaki, H.;
Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige,
T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med.
Chem. 2006, 49, 7854)
Example 2
Synthesis of Fragment B
[0342] Triazolyl based fragment B, that is compounds 13(a-p),
16(a-d), 19(a-d), 23(a-h), 24(a-f) and 25 (a-d) were synthesized by
following method reported in the literature (Boechat, N.; Ferreira,
V. F.; Ferreira, S. B.; Ferreira, M. L. G.; Silva, F. C.; Bastos,
M. M.; Costa, M. S.; Lourenc-o, M. C. S.; Pinto, A. C.; Krettli, A.
U.; Aguiar, A. C.; Teixeira, B. M.; Silva, N. V.; Martins, P. R.
C.; Bezerra, F. A. F. M.; Camilo, A. L. S.; Silva, G. P.; Costa, C.
C. P.; J. Med. Chem. 2011, 54, 5988-5999) as shown in the scheme 2
(provided in FIG. 5), in scheme 3 (provided in FIG. 6), in scheme 4
(provided in FIG. 7), in scheme 6 (provided in FIG. 9), in scheme 7
(provided in FIG. 10) and in scheme 8 (provided in FIG. 11),
respectively. Tetrazolyl based fragment B, that is compounds
30(a-f) and 36 (a-d) were synthesized by following method reported
in literature (Aldhoun, M.; Massi, A.; Dondoni, A.; J. Org. Chem.
2008, 73, 9565-9575) as shown in scheme 10 (provided in FIG. 13)
and in scheme 12 (provided in FIG. 15), respectively. Similarly,
isoxazolyl based fragment B, that is compounds 41(a-l) and 42(a-j)
were synthesized from commercially available starting material by
following the method reported in the literature (Himo, F.; Lovell,
F.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K.
B.; Fokin, V. V.; J. Am. Chem. Soc. 2005, 127, 210-216) as shown in
scheme 14 (provided in FIG. 17) and in scheme 16 (provided in FIG.
19), respectively.
Example 3
Synthesis of Fragment C
[0343] First uridyl based fragment C, that is compound 45(a-j) was
synthesized from commercially available starting materials by
following the method reported in literature (Valgeirsson, J.;
Nielsen, E.; Peters, D.; Varming, T.; Mathiesen, C.; Kristensen, A.
S.; Madsen, U.; J. Med. Chem. 2003, 46, 5835) as shown in scheme 18
(provided in FIG. 21). Sulphonamide based fragment C, that is
compounds 49(a-f) and 53(a-j) were successfully synthesized by
following method reported in the literature (Moreno-Diaz, H.;
Villalobos-Molina, R.; Ortiz-Andrade, R.; Diaz-Coutin, D.;
Medina-Franco, J. L.; Webster, S. P.; Binnie, M.; Estrada-Soto, S.;
Ibarra-Barajas, M.; Leon-Rivera, I.; Navarrete-Vazquez, G.; Bioorg.
Med. Chem. Lett. 2008, 18, 2871-2877) as shown in scheme 20
(provided in FIG. 23) and in scheme 22 (provided in FIG. 25),
respectively.
Example 4
Synthesis of Compound of Formula 1
[0344] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0345] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in
N,N-dimethylformamide (3 mL), 60% sodium hydride (0.022 g, 0.562
mmol) was added at 0.degree. C. portionwise to obtain a mixture.
After the mixture was stirred at 50.degree. C. for 12 hrs under a
nitrogen atmosphere, the mixture was cooled in an ice bath and
carefully quenched with ethyl acetate (2.3 mL) and ice water (0.5
mL). The thus-obtained mixture was poured into water (30 mL) and
extracted with ethylacetate, washed twice with brine solution and
dried under vacuum to obtain a crude product. This crude product
was purified by silica gel column chromatography using a
dichloromethane and ethyl acetate mixture as solvent to obtain
compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6) and
(IIC1-10).
Example 5
Synthesis of Compound of Formula 1
[0346] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0347] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30 (a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in
N,N-dimethylformamide (3 mL), cesium carbonate (0.562 mmol) was
added at 0.degree. C. portionwise to obtain a mixture. After the
mixture was stirred at 80.degree. C. for 12 hrs under a nitrogen
atmosphere, the mixture was cooled in an ice bath. The mixture was
then poured into ice water (30 mL) and extracted with ethylacetate,
washed twice with brine solution and dried under vacuum to obtain a
crude product. This crude product was purified by silica gel column
chromatography using a dichloromethane and ethyl acetate mixture as
solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22),
(IIA1-10), (IIB1-6) and (IIC1-10).
Example 6
Synthesis of Compound of Formula 1
[0348] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0349] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in THF
(3 mL), 60% sodium hydride (0.022 g, 0.562 mmol) was added at
0.degree. C. portionwise to obtain a mixture. After the mixture was
stirred at 80.degree. C. for 24 hrs under a nitrogen atmosphere,
the mixture was cooled in an ice bath and carefully quenched with
ethyl acetate (2.3 mL) and ice water (0.5 mL). The thus-obtained
mixture was poured into water (30 mL) and extracted with
ethylacetate, washed twice with brine solution and dried under
vacuum to obtain a crude product. This crude product was purified
by silica gel column chromatography using a dichloromethane and
ethyl acetate mixture as solvent to obtain compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
Example 7
Synthesis of Compound of Formula 1
[0350] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0351] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in ACN
(3 mL), potassium carbonate (0.562 mmol) was added at 0.degree. C.
portionwise to obtain a mixture. After the mixture was stirred at
80.degree. C. for 24 hrs under a nitrogen atmosphere, the mixture
was cooled in an ice bath. The mixture was poured into water (30
mL) and extracted with ethylacetate, washed twice with brine
solution and dried under vacuum to obtain a crude product. This
crude product was purified by silica gel column chromatography
using a dichloromethane and ethyl acetate mixture as solvent to
obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6),
(IIC1-10).
Example 8
Synthesis of Compound of Formula 1
[0352] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0353] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in ACN
(3 mL), cesium carbonate (0.562 mmol) was added at 0.degree. C.
portionwise to obtain a mixture. After the mixture was stirred at
80.degree. C. for 24 hrs under a nitrogen atmosphere, the mixture
was cooled in an ice bath. The mixture was poured into water (30
mL) and extracted with ethylacetate, washed twice with brine
solution and dried under vacuum to obtain a crude product. This
crude product was purified by silica gel column chromatography
using a dichloromethane and ethyl acetate mixture as solvent to
obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6),
(IIC1-10).
Example 9
Synthesis of Compound of Formula 1
[0354] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0355] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in
Acetone (3 mL), potassium carbonate (0.562 mmol) was added at
0.degree. C. portionwise to obtain a mixture. After the mixture was
stirred at 60.degree. C. for 18 hrs under a nitrogen atmosphere,
the mixture was cooled in an ice bath. The mixture was poured into
water (30 mL) and extracted with ethylacetate, washed twice with
brine solution and dried under vacuum to obtain a crude product.
This crude product was purified by silica gel column chromatography
using a dichloromethane and ethyl acetate mixture as solvent to
obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6),
(IIC1-10).
Example 10
Synthesis of the Compound of Formula 1
[0356] General Procedure for the Preparation of Compounds (IA1-42),
(IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
[0357] To a mixture of compound 9 (0.127 g, 0.586 mmol) and a
compound selected from the group consisting of compounds 13(a-p),
16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d),
41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j)(0.468 mmol) in DCM
(5 mL), 60% sodium hydride (0.022 g, 0.562 mmol) was added at
0.degree. C. portionwise to obtain a mixture. After the mixture was
stirred at 40.degree. C. for 24 hrs under a nitrogen atmosphere,
the mixture was cooled in an ice bath and carefully quenched with
ethyl acetate (2.3 mL) and ice water (0.5 mL). The thus-obtained
mixture was poured into water (30 mL) and extracted with
ethylacetate, washed twice with brine solution and dried under
vacuum to obtain a crude product. This crude product was purified
by silica gel column chromatography using a dichloromethane and
ethyl acetate mixture as solvent to obtain (IA1-42), (IB1-10),
(IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
(R)-2-{4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenoxy)methyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole (compound IA1, Table 1, FIG.
8)
##STR00019##
[0359] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.5 Hz), 7.41 (m, 1H), 7.45 (d, 2H, J=7.5 Hz), 7.51 (m, 2H),
7.79 (m, 2H), 8.08 (s, 1H), 9.08 (s, 1H); MS (ESI+): m\z
418.14.
(R)-2-{4-[4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA2, Table 1,
FIG. 8)
##STR00020##
[0361] TLC (DCM: EtOAc 1:9): R.sub.f=0.32; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.25 (t, 3H, J=8), 1.86 (s, 3H), 2.60 (m,
3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69
(d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.35 (d, 1H, J=7.8),
7.45 (d, 2H, J=7.5 Hz), 7.74 (d, 2H, J=7.8), 8.09 (s, 1H), 9.10 (s,
1H); MS (ESI+): m\z 446.17.
(R)-2-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA3, Table 1,
FIG. 8)
##STR00021##
[0363] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.97 (d,
2H, J=7.6 Hz), 7.30 (m, 2H), 7.45 (d, 2H, J=7.6 Hz), 8.08 (s, 1H),
8.15 (m, 2H), 9.10 (s, 1H); MS (ESI+): m\z 436.13.
(R)-2-{4-[4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA4, Table 1,
FIG. 8)
##STR00022##
[0365] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.6 Hz), 7.28 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.49 (m, 1H),
7.71-7.77 (m, 2H), 8.08 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z
436.13.
(R)-2-{4-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA5,
Table 1, FIG. 8)
##STR00023##
[0367] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.99 (d,
2H, J=7.6 Hz), 7.05 (d, 2H, J=7.8 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.55
(d, 2H, J=7.8 Hz), 8.08 (s, 1H), 8.96 (s, 1H); MS (ESI+): m\z
502.12.
(R)-2-{4-[4-(2-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA6,
Table 1, FIG. 8)
##STR00024##
[0369] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.41 (d, 1H, J=10.8 Hz),
4.52 (dd, 2H, J=21.1, 10.6 Hz), 4.70 (d, 1H, J=10.8 Hz), 6.97 (d,
2H, J=7.6 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.68 (d, 2H, J=7.9 Hz), 7.72
(d, 2H, J=7.9 Hz), 8.08 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z
486.13.
(R)-2-{4-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA7, Table
1, FIG. 8)
##STR00025##
[0371] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 4.45 (d, 1H, J=10.8 Hz),
4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.79 (m,
1H), 6.95 (d, 2H, J=7.6 Hz), 7.07 (m, 2H, J=7.9 Hz), 7.45 (d, 2H,
J=7.6 Hz), 7.75 (d, 2H, J=7.9 Hz), 8.08 (s, 1H), 9.09 (s, 1H); MS
(ESI+): m\z 454.12.
(R)-2-{4-[4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA8, Table 1,
FIG. 8)
##STR00026##
[0373] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.86 (s, 3H), 2.15 (s, 3H), 4.45 (d, 1H,
J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8
Hz), 6.95 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=7.8 Hz), 7.45 (d, 2H,
J=7.6 Hz), 7.78 (d, 2H, J=7.8 Hz), 8.15 (s, 1H), 8.99 (s, 1H); MS
(ESI+): m\z 432.12.
(R)-2-{4-[4-(4-isopropylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-d-
ihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA9, Table
1, FIG. 8)
##STR00027##
[0375] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.35 (d, 6H, J=8.5 Hz), 1.86 (s, 3H),
2.15 (m, 1H, J=8.5 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H,
J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz),
7.30 (d, 2H, J=7.8 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.78 (d, 2H, J=7.8
Hz), 8.15 (s, 1H), 8.99 (s, 1H); MS (ESI+): m\z 460.19.
[0376]
(R)-2-{4-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA10,
Table 1, FIG. 8):
##STR00028##
[0377] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.85 (s, 3H), 4.45 (d, 1H, J=10.8 Hz),
4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.6 Hz), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.49-7.52 (m,
3H), 8.15 (s, 1H), 9.01 (s, 1H); MS (ESI+): m\z 436.13.
(R)-2-{4-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IA11, Table 1,
FIG. 8)
##STR00029##
[0379] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.85 (s, 3H), 4.15 (s, 3H), 4.45 (d, 1H,
J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8
Hz), 6.95 (d, 2H, J=7.6 Hz), 7.09 (d, 2H, J=7.75 Hz), 7.45 (d, 2H,
J=7.6 Hz), 7.68 (d, 2H, J=7.75 Hz), 8.15 (s, 1H), 8.89 (s, 1H); MS
(ESI+): m\z 448.15.
(R)-2-{4-[4-(3-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IA12,
Table 1, FIG. 8)
##STR00030##
[0381] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.6 Hz), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.45-7.50 (m,
3H), 8.15 (s, 1H), 8.92 (s, 1H); MS (ESI+): m\z 502.12.
(R)-2-{4-[4-(3-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IA13,
Table 1, FIG. 8)
##STR00031##
[0383] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.88 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.6 Hz), 7.40 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.47-7.50 (m,
3H), 8.10 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z 486.13.
(R)-2-{4-[4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IA14, Table 1,
FIG. 8)
##STR00032##
[0385] TLC (DCM: EtOAc 1:9): R.sub.f=0.20; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.6 Hz), 7.36 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.85 (m, 1H),
8.10 (s, 1H), 8.40 (m, 1H), 8.65 (m, 1H), 9.01 (s, 1H); MS (ESI+):
m\z 419.13.
(R)-2-{4-[4-pentyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IA15, Table 1, FIG.
8)
##STR00033##
[0387] TLC (DCM: EtOAc 1:9): R.sub.f=0.45; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 0.91 (m, 3H), 1.15 (m, 2H), 1.21 (m, 4H),
1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H,
J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz),
7.45 (d, 2H, J=7.6 Hz), 7.62 (s, 1H), 7.95 (s, 1H); MS (ESI+): m\z
412.19.
(R)-2-{4-[4-heptyl-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IA16, Table 1, FIG.
8)
##STR00034##
[0389] TLC (DCM: EtOAc 1:9): R.sub.f=0.50; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.09 (m, 3H), 1.15 (m, 2H), 1.21-1.24 (m,
8H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd,
2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6
Hz), 7.45 (d, 2H, J=7.6 Hz), 7.60 (s, 1H), 7.95 (s, 1H); MS (ESI+):
m\z 440.22.
(R)-2-{3-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA17, Table 2,
FIG. 8)
##STR00035##
[0391] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s,
1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.30 (d, 2H, J=7.6
Hz), 8.15 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 8.98 (s, 1H); MS (ESI+):
m\z 436.13.
(R)-2-{3-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA18,
Table 2, FIG. 8)
##STR00036##
[0393] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s,
1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6
Hz), 8.11 (d, 2H, J=7.6 Hz), 8.15 (s, 1H), 9.08 (s, 1H); MS (ESI+):
m\z 486.13.
(R)-2-{3-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA19,
Table 2, FIG. 8)
##STR00037##
[0395] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s,
1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.35 (d, 2H, J=7.6
Hz), 7.82 (d, 2H, J=7.6 Hz), 8.05 (s, 1H), 8.89 (s, 1H); MS (ESI+):
m\z 502.12.
(R)-2-{3-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA20, Table
2, FIG. 8)
##STR00038##
[0397] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s,
1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.25 (m, 2H, J=7.9
Hz), 7.45 (d, 2H, J=7.6 Hz), 7.75 (d, 2H, J=7.9 Hz), 8.05 (s, 1H),
8.93 (s, 1H); LC MS (ESI+): m\z 454.12.
(R)-2-{2-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA21, Table 2,
FIG. 8)
##STR00039##
[0399] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.79 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (m,
1H), 7.14 (m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.48 (d, 2H, J=7.6
Hz), 8.05 (d, 2H, J=7.6 Hz), 8.12 (s, 1H), 8.98 (s, 1H); MS (ESI+):
m\z 436.13.
(R)-2-{2-[4-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA22,
Table 2, FIG. 8)
##STR00040##
[0401] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; H NMR (400 MHz, Acetone
d.sub.6): .delta. 1.87. (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd,
2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (m, 1H), 7.14
(m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.68 (d, 2H, J=7.6 Hz), 8.05
(d, 2H, J=7.6 Hz), 8.12 (s, 1H), 9.08 (s, 1H); MS (ESI+): m\z
486.13.
(R)-2-{2-[4-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl-
}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA23,
Table 2, FIG. 8)
##STR00041##
[0403] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.85 (s, 3H), 4.37 (d, 1H, J=10.8 Hz),
4.52 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.97 (m,
1H), 7.14 (m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.34 (d, 2H, J=7.6
Hz), 7.85 (d, 2H, J=7.6 Hz), 8.02 (s, 1H), 8.87 (s, 1H); MS (ESI+):
m\z 502.12.
(R)-2-{2-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA24, Table
2, FIG. 8)
##STR00042##
[0405] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.89 (s, 3H), 4.35 (d, 1H, J=10.8 Hz),
4.49 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.74 (s,
1H), 6.95 (m, 1H), 7.07 (d, 1H, J=8.05 Hz), 7.14 (m, 1H), 7.20 (m,
1H), 7.45 (m, 2H), 7.75 (d, 2H, J=8.05 Hz), 8.05 (s, 1H), 8.90 (s,
1H); MS (ESI+): m\z 454.12.
(R)-2-{4-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA25, Table 3, FIG. 12)
##STR00043##
[0407] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=10.3 Hz), 4.16
(d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2
Hz), 5.28 (s, 2H), 7.00 (m, 4H), 7.17 (d, 2H, J=8.7 Hz), 7.58 (s,
1H), 7.66 (d, 2H, J=9.0 Hz), 7.99 (s, 1H); MS (ESI+): m\z
532.13.
(R)-2-{4-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA26,
Table 3, FIG. 12)
##STR00044##
[0409] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.16
(d, 1H, J=10.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3
Hz), 5.25 (s, 2H), 6.94-7.02 (m, 6H), 7.59 (s, 1H), 7.65 (d, 2H,
J=8.8 Hz), 7.98 (s, 1H); MS (ESI+): m\z 466.14.
(R)-2-{4-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA27, Table 3, FIG. 12)
##STR00045##
[0411] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.16
(d, 1H, J=10.2 Hz), 4.31 (d, 1H, J=10.2 Hz), 4.52 (d, 1H, J=10.2
Hz), 5.33 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.10 (d, 2H, J=8.5 Hz),
7.57 (d, 2H, J=7.0 Hz), 7.35 (s, 1H), 7.66 (d, 2H, J=9.0 Hz), 7.99
(s, 1H); MS (ESI+): m\z 516.14.
(R)-2-{4-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA28,
Table 3, FIG. 12)
##STR00046##
[0413] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=11.4 Hz), 4.16
(d, 1H, J=11.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3
Hz), 5.36 (s, 2H), 6.96-6.92 (m, 1H), 6.99 (d, 2H, J=9.0 Hz),
7.09-7.13 (m, 2H), 7.16 (t, 1H, J=7.9 Hz), 7.59 (s, 1H), 7.66 (d,
2H, J=8.1 Hz), 8.03 (s, 1H); MS (ESI+): m\z 466.14.
(R)-2-{4-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA29,
Table 3, FIG. 12)
##STR00047##
[0415] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 2.29 (s, 3H), 4.09 (d, 1H,
J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53
(d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.92 (d, 2H, J=8.5 Hz), 6.98 (d,
2H, J=8.9 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.58 (s, 1H), 7.65 (d, 2H,
J=8.9 Hz), 7.98 (s, 1H); MS (ESI+): m\z 462.17.
(R)-2-{4-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA30, Table 3, FIG. 12)
##STR00048##
[0417] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.21 (d, 6H, J=8.82 Hz), 1.81 (s, 3H), 2.12
(m, 1H, J=8.82 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2
Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.22 (s,
2H), 6.92 (d, 2H, J=8.6 Hz), 6.98 (d, 2H, J=8.8 Hz), 7.17 (d, 2H,
J=8.6 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.98 (s, 1H); MS
(ESI+): m\z 490.20.
(R)-2-{4-[4-(4-ethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA31,
Table 3, FIG. 12)
##STR00049##
[0419] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.21 (t, 3H, J=7.6 Hz), 1.83 (s, 3H), 2.60 (m,
2H, J=7.6 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz),
4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.27 (s, 2H),
6.94 (d, 2H, J=8.5 Hz), 6.98 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=8.5
Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=9.0 Hz), 7.98 (s, 1H); MS (ESI+):
m\z 476.18.
(R)-2-{4-[4-(4-sec-butylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA32, Table 3, FIG. 12)
##STR00050##
[0421] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 0.81 (t, 3H, J=8.85 Hz), 1.21 (d, 2H, J=8.95
Hz), 1.58-1.51 (m, 3H, J=8.85 Hz), 1.82 (s, 3H), 2.61 (m, 1H,
J=8.95 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32
(d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.23 (s, 2H), 6.96 (m,
4H), 7.12 (d, 2H, J=8.6 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=8.7 Hz),
7.98 (s, 1H); MS (ESI+): m\z 504.21.
(R)-2-{3-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA33, Table 3, FIG. 12)
##STR00051##
[0423] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.08 (d, 1H, J=10.2 Hz), 4.18
(d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.28 (s, 2H), 6.93 (m, 1H), 7.02 (d, 2H, J=9.1 Hz), 7.17 (d,
2H, J=8.9 Hz), 7.34 (m, 2H), 7.44 (m, 1H), 7.57 (s, 1H), 8.05 (s,
1H); MS (ESI+): m\z 532.13.
(R)-2-{3-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA34,
Table 3, FIG. 12)
##STR00052##
[0425] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.08 (d, 1H, J=10.2 Hz), 4.18
(d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.25 (s, 2H), 6.90-7.03 (m, 5H), 7.33 (m, 2H), 7.43 (m, 1H),
7.57 (s, 1H), 8.04 (s, 1H); MS (ESI+): m\z 466.14.
(R)-2-{3-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA35, Table 3, FIG. 12)
##STR00053##
[0427] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.19
(d, 1H, J=10.2 Hz), 4.36 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2
Hz), 5.29 (s, 2H), 6.93 (m, 1H), 7.02 (d, 2H, J=9.1 Hz), 7.17 (d,
2H, J=8.9 Hz), 7.34 (m, 2H), 7.44 (m, 1H), 7.85 (s; 1H), 8.15 (s,
1H); MS (ESI+): m\z 516.14.
(R)-2-{3-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA36,
Table 3, FIG. 12)
##STR00054##
[0429] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.19
(d, 1H, J=10.2 Hz), 4.36 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2
Hz), 5.29 (s, 2H), 6.93 (m, 1H), 7.05-7.15 (m, 3H), 7.22-7.27 (m,
4H), 7.59 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 466.14.
(R)-2-{3-[4-(4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA37,
Table 3, FIG. 12)
##STR00055##
[0431] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.82 (s, 3H), 2.12 (s, 3H), 4.07 (d, 1H,
J=10.2 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51
(d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.93 (m, 1H), 7.05-7.15 (m, 3H),
7.22-7.27 (m, 4H), 7.60 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z
462.17.
(R)-2-{3-[4-(4-isopropylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethy-
l}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound
IA38, Table 3, FIG. 12)
##STR00056##
[0433] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.21 (d, 6H, J=8.82 Hz), 1.82 (s, 3H), 2.15
(s, 3H), 4.07 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.34 (d,
1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.97 (m,
1H), 7.09-7.18 (m, 3H), 7.22-7.27 (m, 4H), 7.71 (s, 1H), 8.05 (s,
1H); MS (ESI+): m\z 462.17.
(R)-2-{2-[4-(4-trifluoromethoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl]pheno-
xymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA39, Table 3, FIG. 12)
##STR00057##
[0435] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.67 (s, 3H), 3.87 (d, 1H, J=10.2 Hz), 4.09
(d, 1H, J=10.3 Hz), 4.34 (d, 1H, J=10.2 Hz), 4.38 (d, 1H, J=10.3
Hz), 5.16 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.09 (d, 1H, J=8.0 Hz),
7.18 (m, 3H), 7.45 (s, 1H), 7.49 (m, 2H), 7.73 (s, 1H), 8.05 (s,
1H); MS (ESI+): m\z 532.13.
(R)-2-{2-[4-(4-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA40,
Table 3, FIG. 12)
##STR00058##
[0437] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.67 (s, 3H), 3.88 (d, 1H, J=10.2 Hz), 4.09
(d, 1H, J=10.3 Hz), 4.36 (d, 1H, J=10.2 Hz), 4.39 (d, 1H, J=10.3
Hz), 5.19 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.09 (d, 1H, J=8.0 Hz),
7.18 (m, 3H), 7.47 (s, 1H), 7.51 (m, 2H), 7.73 (s, 1H), 8.06 (s,
1H); MS (ESI+): m\z 466.14.
(R)-2-{2-[4-(4-trifluoromethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenox-
ymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole
(compound IA41, Table 3, FIG. 12)
##STR00059##
[0439] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.71 (s, 3H), 3.89 (d, 1H, J=10.2 Hz), 4.09
(d, 1H, J=10.3 Hz), 4.34 (d, 1H, J=10.2 Hz), 4.38 (d, 1H, J=10.3
Hz), 5.16 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.12 (d, 1H, J=8.0 Hz),
7.19 (m, 3H), 7.47 (s, 1H), 7.59 (m, 2H), 7.85 (s, 1H), 8.10 (s,
1H); MS (ESI+): m\z 516.43.
(R)-2-{2-[4-(2-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA42,
Table 3, FIG. 12)
##STR00060##
[0441] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.67 (s, 3H), 3.88 (d, 1H, J=10.2 Hz), 4.09
(d, 1H, J=10.3 Hz), 4.36 (d, 1H, J=10.2 Hz), 4.39 (d, 1H, J=10.3
Hz), 5.19 (m, 2H), 7.03 (m, 1H), 7.09 (d, 1H, J=8.0 Hz), 7.18 (m,
3H), 7.28 (m, 3H) 7.47 (s, 1H), 7.77 (s, 1H), 8.08 (s, 1H); MS
(ESI+): m\z 466.14.
(R)-2-{4-[5-phenyl-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6--
nitroimidazo[2,1-b]oxazole (compound IB1, Table 4, FIG. 14)
##STR00061##
[0443] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.5 Hz), 7.41 (m, 1H), 7.45 (d, 2H, J=7.5 Hz), 7.51 (m, 2H),
7.79 (m, 2H), 9.08 (s, 1H); MS (ESI+): m\z 419.13.
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IB2, Table
4, FIG. 14)
##STR00062##
[0445] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 4.37 (d, 1H, J=10.8 Hz),
4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d,
2H, J=7.8 Hz), 7.05 (d, 2H, J=8.12 Hz), 7.51 (d, 2H, J=7.8 Hz),
7.97 (d, 2H, J=8.12 Hz), 9.05 (s, 1H); MS (ESI+): m\z 503.12.
(R)-2-{4-[5-(4-methylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2-
-methyl-6-nitroimidazo[2,1-b]oxazole(compound IB3, Table 4, FIG.
14)
##STR00063##
[0447] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.83 (s, 3H), 2.30 (s, 3H), 4.39 (d, 1H,
J=10.8 Hz), 4.49 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8
Hz), 6.99 (d, 2H, J=7.8 Hz), 7.29 (d, 2H, J=8.05 Hz), 7.51 (d, 2H,
J=7.8 Hz), 9.07 (s, 1H); MS (ESI+): m\z 433.15.
(R)-2-{4-[5-(4-florophenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2--
methyl-6-nitroimidazo[2,1-b]oxazole (compound IB4, Table 4, FIG.
14)
##STR00064##
[0449] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d,
2H, J=7.8 Hz), 7.05 (d, 2H, J=8.12 Hz), 7.51 (d, 2H, J=7.8 Hz),
7.97 (m, 2H), 9.05 (s, 1H); MS (ESI+): m\z 437.12.
(R)-2-{4-[5-(4-trifluoromethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3--
dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB5, Table
4, FIG. 14)
##STR00065##
[0451] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 4.37 (d, 1H, J=10.8 Hz),
4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.99 (d,
2H, J=7.91 Hz), 7.53 (d, 2H, J=7.91 Hz), 7.68 (d, 2H, J=7.5 Hz),
8.37 (d, 2H, J=7.5 Hz), 9.05 (s, 1H); MS (ESI+): m\z 487.12.
(R)-2-{4-[5-(4-ethylphenyl)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro-2--
methyl-6-nitroimidazo[2,1-b]oxazole (compound IB6, Table 4, FIG.
14)
##STR00066##
[0453] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.21 (t, 3H, J=8.85 Hz), 1.83 (s, 3H),
2.28 (m, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.49 (dd, 2H, J=21.1, 10.6
Hz), 4.66 (d, 1H, J=10.8 Hz), 6.99 (d, 2H, J=7.8 Hz), 7.29 (d, 2H,
J=8.05 Hz), 7.51 (d, 2H, J=7.8 Hz), 9.07 (s, 1H); MS (ESI+): m\z
444.17.
(R)-2-{4-[5-(4-fluorophenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB7, Table 4, FIG.
16)
##STR00067##
[0455] TLC (DCM: EtOAc 2:8): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.95 (d,
2H, J=7.18 Hz), 7.07 (d, 2H, J=7.82 Hz), 7.25 (d, 2H, J=7.82 Hz),
7.45 (d, 2H, J=7.18 Hz), 8.90 (s, 1H); MS (ESI+): m\z 453.12.
(R)-2-{4-[5-(4-trifluoromethylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-
-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB8, Table
4, FIG. 16)
##STR00068##
[0457] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.85 (s, 3H), 4.39 (d, 1H, J=10.8 Hz),
4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.90 (d,
2H, J=7.10 Hz), 7.14 (d, 2H, J=7.53 Hz), 7.45 (d, 2H, J=7.53 Hz),
7.48 (d, 2H, J=7.10 Hz), 8.90 (s, 1H); MS (ESI+): m\z 503.12.
(R)-2-{4-[5-(4-methylphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,3-dihydro--
2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB9, Table 4, FIG.
16)
##STR00069##
[0459] TLC (DCM: EtOAc 2:8): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.83 (s, 3H), 2.30 (s, 3H), 4.36 (d, 1H,
J=10.8 Hz), 4.47 (dd, 2H, J=21.1, 10.6 Hz), 4.62 (d, 1H, J=10.8
Hz), 6.93 (d, 2H, J=7.10 Hz), 7.06 (d, 2H, J=7.35 Hz), 7.09 (d, 2H,
J=7.35 Hz), 7.48 (d, 2H, J=7.10 Hz), 8.88 (s, 1H); MS (ESI+): m\z
449.14.
(R)-2-{4-[5-(4-trifluoromethoxyphenoxy)-1H-tetrazol-1-yl]phenoxymethyl}-2,-
3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IB10,
Table 4, FIG. 16)
##STR00070##
[0461] TLC (DCM: EtOAc 2:8): R.sub.f=0.42; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.82 (s, 3H), 4.35 (d, 1H, J=10.8 Hz),
4.43 (dd, 2H, J=21.1, 10.6 Hz), 4.62 (d, 1H, J=10.8 Hz), 6.82 (d,
2H, J=7.65 Hz), 6.99 (d, 2H, J=7.10 Hz), 7.13 (d, 2H, J=7.65 Hz),
7.51 (d, 2H, J=7.10 Hz), 8.85 (s, 1H); MS (ESI+): m\z 519.11.
(R)-2-{4-[5-phenylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6nitro-
imidazo[2,1-b]oxazole (compound IC1, Table 5, FIG. 18)
##STR00071##
[0463] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.82 (s, 3H), 4.07 (d, 1H, J=10.2 Hz),
4.16 (d, 1H, J=10.0 Hz), 4.31 (d, 1H, J=10.0 Hz), 4.52 (d, 1H,
J=10.2 Hz), 6.78 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.46-7.51 (m,
3H), 7.58 (s, 1H), 7.83 (m, 4H); MS (ESI+): m\z 418.13
(R)-2-{4-[5-(4-ethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole(compound IC2, Table 5, FIG. 18)
##STR00072##
[0465] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.21 (m, 3H), 1.84 (s, 3H), 2.40 (m, 2H),
4.36 (d, 1H, J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H,
J=10.8 Hz), 4.66 (d, 1H, J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.24
(s, 1H), 7.37 (d, 2H, J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.88 (d,
2H, J=8.9 Hz), 7.90 (s, 1H); MS (ESI+): m\z 446.46.
(R)-2-{4-[5-(2,4-difluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-
-methyl-6-nitroimidazo[2,1-b]oxazole(compound IC3, Table 5, FIG.
18)
##STR00073##
[0467] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; H NMR (400 MHz, Acetone
d.sub.6): .delta.1.78 (s, 3H), 4.30 (d, 1H, J=10.8 Hz), 4.38 (d,
1H, J=10.6 Hz), 4.42 (d, 1H, J=10.8 Hz), 4.60 (d, 1H, J=10.6 Hz),
7.03 (d, 2H, J=8.9 Hz), 7.18 (m, 1H), 7.19-7.29 (d, 2H, J=8.5 Hz),
7.86 (d, 2H, J=4.7 Hz), 7.89 (s, 1H), 8.03 (m, 1H); MS (ESI+): m\z
454.14.
(R)-2-{4-[5-(2-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,14]oxazole(compound IC4, Table 5, FIG. 18)
##STR00074##
[0469] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 4.32 (d, 1H, J=10.8 Hz),
4.40 (d, 1H, J=10.6 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.62 (d, 1H,
J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.19-7.29 (d, 2H, J=8.5 Hz),
7.86 (m, 3H), 7.83 (s, 1H), 7.98 (m, 1H); MS (ESI+): m\z
436.12.
(R)-2-{4-[5-(4-trifluoromethylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound 105, Table 5,
FIG. 18)
##STR00075##
[0471] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.89 (s, 3H), 4.38 (d, 1H, J=10.8 Hz),
4.47 (d, 1H, J=10.6 Hz), 4.49 (d, 1H, J=10.8 Hz), 4.68 (d, 1H,
J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.26 (s, 1H), 7.39 (d, 2H,
J=8.5 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.89, (d, 2H, J=8.9 Hz), 7.92
(s, 1H); MS (ESI+): m\z 486.12.
(R)-2-{4-[5-(4-methylphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole(compound 106, Table 5, FIG.
18)
##STR00076##
[0473] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.84 (s, 3H), 2.40 (s, 2H), 4.36 (d, 1H,
J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H, J=10.8 Hz), 4.66
(d, 1H, J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.24 (s, 1H), 7.37 (d,
2H, J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.88 (d, 2H, J=8.9 Hz), 7.90
(s, 1H); MS (ESI+): m\z 432.14.
(R)-2-{4-[5-(4-methoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole(compound IC7, Table 5, FIG.
18)
##STR00077##
[0475] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.85 (s, 3H), 3.89 (s, 3H), 4.38 (d, 1H,
J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H, J=10.8 Hz), 4.66
(d, 1H, J=10.6 Hz), 7.10 (m, 4H), 7.17 (s, 1H), 7.88 (m, 4H), 8.02
(s, 1H); MS (ESI+): m\z 448.14.
(R)-2-{4-[5-(3-fluorophenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-met-
hyl-6-nitroimidazo[2,1-b]oxazole(compound IC8, Table 5, FIG.
18)
##STR00078##
[0477] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 4.32 (d, 1H, J=10.8 Hz),
4.40 (d, 1H, J=10.6 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.62 (d, 1H,
J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.17 (s, 1H), 7.19-7.29 (d, 2H,
J=8.5 Hz), 7.86 (m, 2H), 7.83 (s, 1H), 7.98 (m, 2H); MS (ESI+): m\z
436.12.
(R)-2-{4-[5-(pyridin-2-yl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methy-
l-6-nitroimidazo[2,1-b]oxazole (compound IC9, Table 5, FIG. 18)
##STR00079##
[0479] TLC (DCM: EtOAc 1:9): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.82 (s, 3H), 4.34 (d, 1H, J=10.8 Hz),
4.43 (d, 1H, J=10.6 Hz), 4.47 (d, 1H, J=10.8 Hz), 4.64 (d, 1H,
J=10.6 Hz), 7.12 (d, 2H, J=8.9 Hz), 7.19 (s, 1H), 7.29 (d, 2H,
J=8.5 Hz), 7.86 (m, 3H), 7.89 (s, 1H), 8.40 (m, 1H); MS (ESI+): m\z
419.12.
(R)-2-{4-[5-(4-trifluoromethoxyphenyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IC10, Table 5,
FIG. 18)
##STR00080##
[0481] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.83 (s, 3H), 4.33 (d, 1H, J=10.8 Hz),
4.42 (d, 1H, J=10.6 Hz), 4.44 (d, 1H, J=10.8 Hz), 4.64 (d, 1H,
J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.22 (s, 1H), 7.32 (d, 2H,
J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.85 (d, 2H, J=8.9 Hz), 7.90 (s,
1H); MS (ESI+): m\z 502.12.
(R)-2-{4-[5-pentylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitr-
oimidazo[2,1-b]oxazole (compound IC11, Table 5 FIG. 18)
##STR00081##
[0483] TLC (DCM: EtOAc 1:9): R.sub.f=0.45; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.0.91 (m, 3H), 1.15 (m, 2H), 1.21 (m, 4H),
1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H,
J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz),
7.05 (s, 1H), 7.25 (d, 2H, J=7.6 Hz), 7.85 (s, 1H); MS (ESI+): m\z
412.19.
(R)-2-{4-[5-heptylisoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitr-
oimidazo[2,1-b]oxazole (compound IC12, Table 5, FIG. 18)
##STR00082##
[0485] TLC (DCM: EtOAc 1:9): R.sub.f=0.45; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.0.91 (m, 3H), 1.15 (m, 2H), 1.21-1.24 (m,
8H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd,
2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.96 (d, 2H, J=7.6
Hz), 7.07 (s, 1H), 7.26 (d, 2H, J=7.6 Hz), 7.83 (s, 1H); MS (ESI+):
m\z 440.21.
(R)-2-{4-[5-(4-trifluoromethoxyphenoxymethyl)isoxazol-3-yl]phenoxymethyl}--
2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC13,
Table 5, FIG. 20)
##STR00083##
[0487] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.18 (s, 2H), 6.60 (s, 1H), 6.92 (d, 2H, J=8.9 Hz), 6.98 (d,
2H, J=9.2 Hz), 7.18 (d, 2H, J=9.2 Hz), 7.56 (s, 1H), 7.74 (d, 2H,
J=8.9 Hz); MS (ESI+): m\z 532.12.
(R)-2-{4-[5-(4-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC14, Table 5,
FIG. 20)
##STR00084##
[0489] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.16 (s, 2H), 6.58 (s, 1H), 6.90-6.95 (m, 4H), 7.01 (m, 2H),
7.57 (s, 1H), 7.74 (d, 2H, J=8.8 Hz); MS (ESI+): m\z 466.13.
(R)-2-{4-[5-(4-trifluoromethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2-
,3-dihydro-2-methyl-6-nitroimidazo[2,1-]oxazole (compound IC15,
Table 5, FIG. 20)
##STR00085##
[0491] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.24 (s, 2H), 6.61 (s, 1H), 6.92 (d, 2H, J=8.9 Hz), 7.06 (d,
2H, J=8.6 Hz), 7.57 (s, 1H), 7.59 (d, 2H, J=8.6 Hz), 7.75 (d, 2H,
J=8.9 Hz); MS (ESI+): m\z 516.13.
(R)-2-{4-[5-(2-fluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC16, Table 5,
FIG. 20)
##STR00086##
[0493] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.26 (s, 2H), 6.63 (s, 1H), 6.92 (d, 2H, J=8.8 Hz), 6.98 (m,
1H), 7.02-7.09 (m, 2H), 7.12 (m, 1H), 7.57 (s, 1H), 7.75 (d, 2H,
J=8.8 Hz); MS (ESI+): m\z 466.13.
(R)-2-{4-[5-(4-methylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydr-
o-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC17, Table 5,
FIG. 20)
##STR00087##
[0495] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.83 (s, 3H), 2.32 (s, 3H), 4.08 (d, 1H,
J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53
(d, 1H, J=10.3 Hz), 5.19 (s, 2H), 6.60 (s, 1H), 6.92 (m, 4H), 7.13
(d, 2H, J=7.8 Hz), 7.59 (s, 1H), 7.76 (d, 2H, J=8.8 Hz); MS (ESI+):
m\z 462.15.
(R)-2-{4-[5-(4-isopropylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC18, Table 5,
FIG. 20)
##STR00088##
[0497] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (d, 6H, J=6.9 Hz), 1.83 (s, 3H), 2.89 (m,
1H), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.30 (d, 1H,
J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s, 2H), 6.61 (s, 1H),
6.93 (m, 4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s, 1H), 7.75 (d, 2H,
J=7.7 Hz); MS (ESI+): m\z 490.19.
(R)-2-{4-[5-(4-ethylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-
-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC19, Table 5,
FIG. 20)
##STR00089##
[0499] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.23 (m, 3H), 1.83 (s, 3H), 2.85 (m, 2H), 4.09
(d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.30 (d, 1H, J=10.1
Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s, 2H), 6.61 (s, 1H), 6.93 (m,
4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s, 1H), 7.75 (d, 2H, J=7.7 Hz);
MS (ESI+): m\z 476.17.
(R)-2-{4-[5-(4-sec-butylphenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dih-
ydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC20, Table 5,
FIG. 20)
##STR00090##
[0501] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.11 (m, 3H), 1.22 (m, 3H), 1.28 (m, 2H), 1.82
(s, 3H), 2.89 (m, 1H), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1
Hz), 4.30 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s,
2H), 6.61 (s, 1H), 6.93 (m, 4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s,
1H), 7.75 (d, 2H, J=7.7 Hz); MS (ESI+): m\z 504.20.
(R)-2-{4-[5-(phenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IC21, Table 5, FIG.
20)
##STR00091##
[0503] TLC (DCM: EtOAc 1:9): R.sub.f=0.30; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.26 (s, 2H), 6.78 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.51-7.46
(m, 3H), 7.58 (s, 1H), 7.83 (m, 4H); MS (ESI+): m\z 448.14.
(R)-2-{4-[5-(2,4-difluorophenoxymethyl)isoxazol-3-yl]phenoxymethyl}-2,3-di-
hydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IC22, Table
5, FIG. 20)
##STR00092##
[0505] TLC (DCM: EtOAc 1:9): R.sub.f=0.40; .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14
(d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2
Hz), 5.26 (s, 2H), 6.63 (s, 1H), 6.92 (d, 2H, J=8.8 Hz), 7.02-7.09
(m, 2H), 7.57 (s, 1H), 7.75 (d, 2H, J=8.8 Hz), 7.89 (m, 1H); MS
(ESI+): m\z 484.12.
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}urea(compound IIA1, Table 6, FIG. 22)
##STR00093##
[0507] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H,
J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44
(d, 2H, J=9.1 Hz), 7.68 (m, 2H), 7.90 (s, 1H), 8.11 (s, 1H), 8.34
(s, 1H); MS (ESI+): m\z 493.12.
[0508]
(R)-1-(4-ethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-
-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA2, Table 6, FIG.
22):
##STR00094##
[0509] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.21 (t, 3H, J=8.85 Hz), 1.80 (s, 3H),
2.28 (m, 2H, J=8.85 Hz), 4.30 (m, 3H), 4.62 (d, 1H, J=10.8 Hz),
6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=9.1
Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s,
1H); MS (ESI+): m\z 437.17.
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[-
2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA3, Table 6, FIG.
22)
##STR00095##
[0511] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.81 (s, 3H), 4.34 (m, 3H), 4.65 (d, 1H,
J=10.8 Hz), 6.89 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.45
(d, 2H, J=9.1 Hz), 7.68 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s,
1H), 8.34 (s, 1H); MS (ESI+): m\z 477.13.
(R)-1-(4-methylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}urea(compound IIA4, Table 6, FIG. 22)
##STR00096##
[0513] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 2.38 (s, 3H), 4.32 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4
Hz), 7.47 (d, 2H, J=9.1 Hz), 7.65 (d, 2H, J=9.1 Hz), 7.90 (s, 1H),
8.10 (s, 1H), 8.32 (s, 1H); MS (ESI+): m\z 423.15.
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}urea(compound IIA5, Table 6, FIG. 22)
##STR00097##
[0515] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.82 (s, 3H), 3.76 (s, 3H), 4.33 (m, 3H),
4.62 (d, 1H, J=10.7 Hz), 6.86 (m, 4H), 7.44 (m, 4H), 7.91 (s, 1H),
8.03 (s, 2H; MS (ESI+): m\z 439.15.
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}urea(compound IIA6, Table 6, FIG.
22)
##STR00098##
[0517] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H,
J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44
(d, 2H, J=9.1 Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s,
1H), 8.34 (s, 1H); MS (ESI+): m\z 493.12.
(R)-1-(4-methoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]ox-
azol-2-yl)methoxyphenyl}thiourea(compound IIA7, Table 6, FIG.
22)
##STR00099##
[0519] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 3.73 (s, 3H), 4.33 (m, 3H),
4.60 (d, 1H, J=10.7 Hz), 6.83 (m, 4H), 7.40 (m, 4H), 7.89 (s, 1H),
8.00 (s, 2H; MS (ESI+): m\z 455.13.
(R)-1-(4-trifluoromethoxyphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo-
[2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA8, Table 6,
FIG. 22)
##STR00100##
[0521] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H,
J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44
(d, 2H, J=9.1 Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s,
1H), 8.34 (s, 1H); MS (ESI+): m\z 509.10.
(R)-1-(4-fluorophenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxa-
zol-2-yl)methoxyphenyl}thiourea(compound IIA9, Table 6, FIG.
22)
##STR00101##
[0523] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 4.30 (m, 3H), 4.60 (d, 1H,
J=10.8 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.42
(d, 2H, J=9.1 Hz), 7.65 (m, 2H), 7.90 (s, 1H), 8.10 (s, 1H), 8.32
(s, 1H); MS (ESI+): m\z 443.11.
(R)-1-(4-trifluoromethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[-
2,1-b]oxazol-2-yl)methoxyphenyl}thiourea(compound IIA10, Table 6,
FIG. 22)
##STR00102##
[0525] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 4.34 (m, 3H), 4.65 (d, 1H,
J=10.8 Hz), 6.89 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.45
(d, 2H, J=9.1 Hz), 7.68 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s,
1H), 8.34 (s, 1H); MS (ESI+): m\z 493.10.
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N-(-
p-tolyl) benzenesulfonamide(compound IIB1, Table 7, FIG. 24)
##STR00103##
[0527] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.80 (s, 3H), 2.38 (s, 3H), 4.01 (brs,
1H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.85
Hz), 7.02 (d, 2H, J=7.85 Hz), 7.12 (d, 2H, J=7.25 Hz), 7.64 (d, 2H,
J=7.25 Hz), 7.90 (s, 1H); MS (ESI+): m\z 444.11.
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N-(-
4 trifluoro methoxyphenyl)benzenesulfonamide(compound IIB2, Table
7, FIG. 24)
##STR00104##
[0529] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.81 (s, 3H), 4.03 (brs, 1H), 4.33 (m,
3H), 4.64 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.45 Hz), 7.12 (d, 2H,
J=7.05 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89 (s, 1H); MS (ESI+): m\z
514.08.
(R)-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxy}-N-(-
4 trifluoro methylphenyl)benzenesulfonamide(compound IIB3, Table 7,
FIG. 24)
##STR00105##
[0531] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.83 (s, 3H), 4.05 (brs, 1H), 4.35 (m,
3H), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.05 Hz), 7.12 (d, 2H,
J=7.26 Hz), 7.30 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.26 Hz), 7.91
(s, 1H); MS (ESI+): m\z 498.08.
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)me-
thoxy}-N-phenylbenzenesulfonamide(compound IIB4, Table 7, FIG.
24)
##STR00106##
[0533] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 3.20 (s, 3H), 4.32 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 6.78-6.92 (m, 5H), 7.02 (d, 2H, J=7.25
Hz), 7.64 (d, 2H, J=7.25 Hz), 7.85 (s, 1H); MS (ESI+): m\z
444.11.
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydrohnidazo[2,1-b]oxazol-2-yl)me-
thoxy}-N-(p-tolyl)benzenesulfonamide(compound IIB5, Table 7, FIG.
24)
##STR00107##
[0535] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 2.34 (s, 3H), 3.20 (s, 3H),
4.33 (m, 3H), 4.63 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.85 Hz),
7.02 (d, 2H, J=7.85 Hz), 7.12 (d, 2H, J=7.25 Hz), 7.64 (d, 2H,
J=7.25 Hz), 7.90 (s, 1H); MS (ESI+): m\z 458.13.
(R)--N-methyl-4-{(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)me-
thoxy}-N-(p-trifluoromethylphenyl)benzenesulfonamide(compound IIB6,
Table 7, FIG. 24)
##STR00108##
[0537] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.83 (s, 3.20 (s, 3H), 4.35 (m, 3H), 4.65
(d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.05 Hz), 7.12 (d, 2H, J=7.26
Hz), 7.30 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.26 Hz), 7.91 (s,
1H); MS (ESI+): m\z 512.10.
(R)-2-{4-(4-phenylpiperazin-1-yl)sulfonylphenoxymethyl}-2,3-dihydro-2-meth-
yl-6-nitroimidazo[2,1-b]oxazole (compound IIC1, Table 8, FIG.
26)
##STR00109##
[0539] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.81 (s, 3H), 3.19 (s, 8H), 4.32 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 7.01 (m, 2H), 7.05-7.24 (m, 3H), 7.12 (d,
2H, J=7.05 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89 (s, 1H); MS (ESI+):
m\z 499.15.
(R)-2-{4-[4-(4-fluorophenylpiperazin-1-yl)sulfonylphenoxymethyl}-2,3-dihyd-
ro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC2, Table 8,
FIG. 26)
##STR00110##
[0541] TLC (DCM: EtOAc 2:8): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.82 (s, 3H), 3.21 (s, 8H), 4.33 (m, 3H),
4.63 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.15 Hz), 7.12 (d, 2H,
J=7.05 Hz), 7.25 (m, 2H), 7.64 (d, 2H, J=7.05 Hz), 7.91 (s, 1H); MS
(ESI+): m\z 517.14.
(R)-2-{4-[4-(3-chlorophenyl)piperazin-1-yl]sulfonylphenoxymethyl}-2,3-dihy-
dro-2-methyl-6-nitroimidazo[2,1-b]oxazole(compound IIC3, Table 8,
FIG. 26)
##STR00111##
[0543] TLC (DCM: EtOAc 2:8): R.sub.f=0.35; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 3.20 (s, 8H), 4.31 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 6.94-7.12 (m, 3H), 7.21 (d, 2H, J=7.05
Hz), 7.35 (m, 1H), 7.64 (d, 2H, J=7.05 Hz), 7.90 (s, 1H); MS
(ESI+): m\z 533.11.
(R)-2-{4-[4-(4-trifluoromethoxyphenylpiperazin-1-yl)sulfonylphenoxymethyl}-
-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IIC4,
Table 8, FIG. 26)
##STR00112##
[0545] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 3.19 (s, 8H), 4.31 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.15 Hz), 7.01 (d, 2H,
J=7.05 Hz), 7.25 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89
(s, 1H); MS (ESI+): m\z 583.13.
(R)-ethyl-{4-[4-(2-methyl-6-nitro-2,3-dihydro
imidazo[2,1-b]oxazol-2yl)methoxyphenyl]
sulfonyl}piperazine-1-carboxylate(compound IIC5, Table 8, FIG.
26)
##STR00113##
[0547] TLC (DCM: EtOAc 2:8): R.sub.f=0.20; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.29 (m, 3H), 1.80 (s, 3H), 3.25 (s, 8H),
4.13 (m, 2H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d, 2H,
J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+): m\z
495.14.
(R)-{4-[4-(2-methyl-6-nitro-2,3-dihydrohnidazo[2,1-b]oxazol-2yl)methoxyphe-
nyl] sulfonyl}piperazine-1-yl(phenyl)methanone(compound IIC6, Table
8, FIG. 26)
##STR00114##
[0549] TLC (DCM: EtOAc 2:8): R.sub.f=0.20; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.81 (s, 3H), 3.19 (s, 8H), 4.31 (m, 3H),
4.62 (d, 1H, J=10.8 Hz), 6.94 (m, 3H), 7.01 (d, 2H, J=7.05 Hz),
7.30 (m, 2H), 7.64 (d, 2H, J=7.05 Hz), 7.91 (s, 1H); MS (ESI+): m\z
527.15.
(R)-2-{4-(piperidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-nit-
roimidazo[2,1-b]oxazole (compound IIC7, Table 8, FIG. 28)
##STR00115##
[0551] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.53 (m, 211), 1.59 (m, 4H), 1.80 (s,
3H), 3.07 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d,
2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+):
m\z 422.13.
(R)-2-{4-[(4-phenylpiperidin-1-yl)sulfonyl]phenoxymethyl}-2,3-dihydro-2-me-
thyl-6-nitroimidazo[2,1-b]oxazole (compound IIC8, Table 8, FIG.
26)
##STR00116##
[0553] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta.1.59 (m, 4H), 1.80 (s, 3H), 2.59 (m, 1H),
3.17 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.95-7.05 (m,
5H), 7.12 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.93 (s,
1H); MS (ESI+): m\z 498.16.
(R)-2-{4-(pyrrolidin-1-ylsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-ni-
troimidazo[2,1-b]oxazole (compound IIC9, Table 8, FIG. 26)
##STR00117##
[0555] TLC (DCM: EtOAc 2:8): R.sub.f=0.40; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.92 (m, 4H), 1.80 (s, 3H), 3.07 (m, 4H),
4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d, 2H, J=7.15 Hz),
7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+): m\z 408.11.
(R)-2-{4-(morpholinsulfonyl)phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimi-
dazo[2,1-b]oxazole (compound IIC10, Table 8, FIG. 26)
##STR00118##
[0557] TLC (DCM: EtOAc 2:8): R.sub.f=0.30; .sup.1H NMR (400 MHz,
Acetone d.sub.6): .delta. 1.80 (s, 3H), 2.96 (m, 4H), 3.67 (m, 4H),
4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.14 (d, 2H, J=7.15 Hz),
7.65 (d, 2H, J=7.15 Hz), 7.99 (s, 1H); MS (ESI+): m\z 424.11.
[0558] Table 1 shows the structure of representative compounds
IA1-IA16 belonging to formula IA and synthesized as per scheme 5
provided in FIG. 8.
TABLE-US-00001 TABLE 1 Entry Code Structure 1 IA1 ##STR00119## 2
IA2 ##STR00120## 3 IA3 ##STR00121## 4 IA4 ##STR00122## 5 IA5
##STR00123## 6 IA6 ##STR00124## 7 IA7 ##STR00125## 8 IA8
##STR00126## 9 IA9 ##STR00127## 10 IA10 ##STR00128## 11 IA11
##STR00129## 12 IA12 ##STR00130## 13 IA13 ##STR00131## 14 IA14
##STR00132## 15 IA15 ##STR00133## 16 IA16 ##STR00134##
[0559] Table 2 shows the structure of representative compounds
IA17-IA24 belonging to formula IA and synthesized as per scheme 5
provided in FIG. 8.
TABLE-US-00002 TABLE 2 Entry Code Structure 1 IA17 ##STR00135## 2
IA18 ##STR00136## 3 IA19 ##STR00137## 4 IA20 ##STR00138## 5 IA21
##STR00139## 6 IA22 ##STR00140## 7 IA23 ##STR00141## 8 IA24
##STR00142##
[0560] Table 3 shows the structure of representative compounds
IA25-IA42 belonging to formula IA and synthesized as per scheme 9
provided in FIG. 12.
TABLE-US-00003 TABLE 3 Entry Code Structure 1 IA25 ##STR00143## 2
IA26 ##STR00144## 3 IA27 ##STR00145## 4 IA28 ##STR00146## 5 IA29
##STR00147## 6 IA30 ##STR00148## 7 IA31 ##STR00149## 8 IA32
##STR00150## 9 IA33 ##STR00151## 10 IA34 ##STR00152## 11 IA35
##STR00153## 12 IA36 ##STR00154## 13 IA37 ##STR00155## 14 IA38
##STR00156## 15 IA39 ##STR00157## 16 IA40 ##STR00158## 17 IA41
##STR00159## 18 IA42 ##STR00160##
[0561] Table 4 shows the structure of representative compounds
IB1-IB10 belonging to formula IB and synthesized as per scheme 11
and scheme 13 provided in FIG. 14 and FIG. 16, respectively.
TABLE-US-00004 TABLE 4 Entry Code Structure 1 IB1 ##STR00161## 2
IB2 ##STR00162## 3 IB3 ##STR00163## 4 IB4 ##STR00164## 5 IB5
##STR00165## 6 IB6 ##STR00166## 7 IB7 ##STR00167## 8 IB8
##STR00168## 9 IB9 ##STR00169## 10 IB10 ##STR00170##
[0562] Table 5 shows the structure of representative compounds
IC1-IC22 belonging to formula IC and synthesized as per scheme 15
and scheme 17 provided in FIG. 18 and FIG. 20, respectively.
TABLE-US-00005 TABLE 5 Entry Code Structure 1 IC1 ##STR00171## 2
IC2 ##STR00172## 3 IC3 ##STR00173## 4 IC4 ##STR00174## 5 IC5
##STR00175## 6 IC6 ##STR00176## 7 IC7 ##STR00177## 8 IC8
##STR00178## 9 IC9 ##STR00179## 10 IC10 ##STR00180## 11 IC11
##STR00181## 12 IC12 ##STR00182## 13 IC13 ##STR00183## 14 IC14
##STR00184## 15 IC15 ##STR00185## 16 IC16 ##STR00186## 17 IC17
##STR00187## 18 IC18 ##STR00188## 19 IC19 ##STR00189## 20 IC20
##STR00190## 21 IC21 ##STR00191## 22 IC22 ##STR00192##
[0563] Table 6 shows the structure of representative compounds
IIA1-IIA10 belonging to formula IIA and synthesized as per scheme
19 provided in FIG. 22.
TABLE-US-00006 TABLE 6 Entries Codes Structures 1 IIA1 ##STR00193##
2 IIA2 ##STR00194## 3 IIA3 ##STR00195## 4 IIA4 ##STR00196## 5 IIA5
##STR00197## 6 IIA6 ##STR00198## 7 IIA7 ##STR00199## 8 IIA8
##STR00200## 9 IIA9 ##STR00201## 10 IIA10 ##STR00202##
[0564] Table 7 shows the structure of representative compounds
IIB1-IIB6 belonging to formula IIB and synthesized as per scheme 21
provided in FIG. 24.
TABLE-US-00007 TABLE 7 Entries Codes Structures 1 IIB1 ##STR00203##
2 IIB2 ##STR00204## 3 IIB3 ##STR00205## 4 IIB4 ##STR00206## 5 IIB5
##STR00207## 6 IIB6 ##STR00208##
[0565] Table 8 shows the structure of representative compounds
IIC1-IIC10 belonging to formula IIC and synthesized as per scheme
23 provided in FIG. 26.
TABLE-US-00008 TABLE 8 Entries Codes Structures 1 IIC1 ##STR00209##
2 IIC2 ##STR00210## 3 IIC3 ##STR00211## 4 IIC4 ##STR00212## 5 IIC5
##STR00213## 6 IIC6 ##STR00214## 7 IIC7 ##STR00215## 8 IIC8
##STR00216## 9 IIC9 ##STR00217## 10 IIC10 ##STR00218##
Biological Evaluation
Example 11
Physiochemical Properties
[0566] The physiochemical properties (log P.sub.0/w, log S, log
Khsa) of the compounds IA1 to IIC10 were evaluated by using the
schrodinger softwere. The detailed results were shown in Table
9.
Example 12
In Vitro Activity of Compounds 1A1 to IIC10 Against M. tuberculosis
H37Rv and Two Clinical Isolates (MDR M. tuberculosis & XDR M.
tuberculosis)
[0567] MIC Determination:
[0568] MIC was determined by broth dilution method against M.
tuberculosis H37Rv (ATCC 27294; American Type Culture Collection,
Manassas, Va.), M. tuberculosis MDR (resistant to isoniazid and
rifampicin) and M. tuberculosis XDR (resistant to isoniazid,
rifampicin, amikacin and moxifloxacin). The bacterial strains were
grown for 10 to 15 days in Middlebrook 7H9 broth (Difco
Laboratories, Detroit, Mich.) supplemented with 0.5% (v/v)
glycerol, 0.25% (v/v) Tween 80 (Himedia, Mumbai India), and 10% ADC
(albumin dextrose catalase; Becton Dickinson, Sparks, MD) under
shaking conditions at 37.degree. C. in 5% CO.sub.2 to facilitate
exponential-phase growth of the organism. Bacterial suspension was
prepared by suspending M. tuberculosis growth in normal saline
containing 0.5% tween 80 and turbidity was adjusted to 1 McFarland
standard which is equivalent to 1.5.times.10.sup.7 CFU/ml. The
2-fold serial dilutions of compounds IA1 to IIC10 were prepared in
Middle brook 7H9 (Difco laboratories) for M. tuberculosis in 100
.quadrature.l per well in 96-well U bottom microtitre plates
(Tarson, Mumbai, India). The above-mentioned bacterial suspension
was further diluted in the growth media and 100 .quadrature.l
volume of this diluted inoculum was added to each well of the plate
resulting in the final inoculum of 5.times.10.sup.5 CFU/ml in the
well and the final concentrations of compound IA1 to IIC10 ranged
from 0.015 to 32 .mu.g/ml. The plates were incubated at 37.degree.
C. for 3-weeks in 5% CO.sub.2. The plates were read visually and
the minimum concentration of the compound showing no turbidity was
recorded as MIC.
[0569] Results:
[0570] Triazolyl containing
6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IA1-IA42, were
screened against both sensitive H.sub.37Rv as well as multi- and
extensive-drug resistant strains of M. tuberculosis, wherein 12
compounds IA3, IA5, IA11, IA12, IA25, IA26, IA27, IA28, IA31, IA32,
IA33 and IA34 showed MIC value of <1.0 .mu.g/ml (results
provided in Table 9). Two compounds IA25 and IA33 showed very
potent MIC of 0.12 .mu.g/ml against sensitive and resistant strains
of M. tuberculosis. Tetrazolyl containing
6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IB1-IB10 showed
MIC of 1 to 4.0 .mu.g/ml against H.sub.37Rv, MDR and XDR M.
tuberculosis. Isoxazolyl containing
6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IC1-IC22 were
also screened against both sensitive H.sub.37Rv as well as multi-
and extensive-drug resistant strains of M. tuberculosis, wherein 11
compounds IC1, IC3, IC7, IC10, IC13, IC14, IC15, IC16, IC17, IC18
and IC22 showed potent MIC value of <1.0 .mu.g/ml. Among these
compounds, three compounds IC1, IC13 and IC14 showed MIC value of
0.06, 0.12 and 0.06 .mu.g/ml respectively against H37Rv M.
Tuberculosis. Uridyl containing 6-nitro-2,3-dihydro
imidazo[2,1-b]-oxazole compounds IIA1-IIA10 were also synthesized
and screened against sensitive H.sub.37Rv as well as multi- and
extensive-drug resistant strains of M. tuberculosis, wherein 4
compounds IIA2, IIA3, IIA4 and IIA6 showed MIC value of <1.0
.mu.g/ml against H.sub.37Rv, MDR and XDR M. tuberculosis.
Sulphanamidyl containing 6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole
compounds IIB1-IIB6 and IIC1-IIC10 were also synthesized and
screened, wherein two compounds IIC8 and IIC10 showed MIC of 0.5
.mu.g/ml against sensitive and resistant strains of M.
tuberculosis. From these medicinal chemistry program, several new
generation nitroimidazole based compounds were identified which
possessed potent MIC against sensitive as well as resistant strain
of M. tuberculosis
Example 13
Cytotoxicity Assay of Compounds IA1 to IIC10
[0571] Cell Culture:
[0572] The study was carried out using macrophage J774 cells line
(ATCC-USA). Cells were grown in Rosewell Park Memorial Institute
Medium (RPMI) containing 10% fetal calf serum (FCS) and
supplemented with 75 mg/litre penicillin, 100 mg/litre
streptomycin, 110 mg/litre Sodium pyruvate, 2.38 gm/litre HEPES,
0.05 mM 2 .beta.-mercaptoethanol, and 2 gm/litre NaHCO.sub.3, in a
humidified atmosphere in 5% CO.sub.2 at 37.degree. C., and were
sub-cultured at 1:4 ratio once a week.
[0573] Cell Treatment:
[0574] Cells were plated at a density of 3.times.10.sup.4
cells/cm.sup.2 and maintained in culture medium for 12 hours. Cells
were seeded onto 96-well flat bottom plates and FCS was reduced to
5% for the experiment. Stock solutions of compounds IA1 to IIC10
were prepared fresh to avoid oxidation. Cells were incubated with
the compounds (40 .mu.g/ml) for 24 hrs.
[0575] Cytotoxicity Assays:
[0576] After the completion of incubation, the medium was removed
and cell viability was evaluated by assaying for the ability of
functional mitochondria to catalyze the reduction of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
to form formazan salt by mitochondrial dehydrogenases, and
determined by Elisa reader at 450 nm (Multiskan Spectrum; Thermo
Electron Corporation, USA). Percentage cytotoxicity was calculated
with respect to the untreated cells.
[0577] Results:
[0578] Compounds IA1 to IIC10 were not toxic up to 40 .mu.g/ml
concentration and the cytotoxicity assay results are shown in Table
9.
[0579] Table 9 shows the physico-chemical properties,
Anti-tuberculosis activity and cytotoxicity of representative
compound shown in tables 1 to 8.
TABLE-US-00009 TABLE 9 MIC (.mu.g/ml) Cytotox- Selec- Com- M. tb M.
tb M. tb icity tivity S. No pound logPo/w logS logKhsa H37Rv MDR
XDR (.mu.g/ml) Index 1. IA1 3.878 -6.155 0.493 4 4 4 >40 >10
2. IA2 4.177 -6.023 0.621 2 4 4 >40 >10 3. IA3 4.103 -6.43
0.537 0.25 0.25 0.25 >40 >10 4. IA4 4.076 -6.338 0.531 1 2 2
>40 ND 5. IA5 4.715 -7.186 0.71 0.5 0.5 0.5 >40 >10 6. IA6
4.624 -6.743 0.678 1.0 1.0 1.0 >40 >10 7. IA7 4.186 -6.494
0.522 2 2 2 >40 ND 8. IA8 4.189 -6.667 0.665 1 1 1 >40 ND 9.
IA9 4.728 -7.192 0.879 1 1 1 >40 ND 10. IA10 4.117 -6.531 0.539
2 2 2 >40 ND 11. IA11 3.921 -6.201 0.465 0.25 0.25 0.25 >40
>10 12. IA12 4.899 -7.385 0.736 0.5 0.5 0.5 >40 >10 13.
IA13 4.721 -7.201 0.712 2 2 2 >40 >10 14. IA14 3.156 -5.559
0.196 2 2 2 >40 >10 15. IA15 4.008 -6.099 0.487 32 32 32
>40 >10 16. IA16 4.686 -6.741 0.713 4 4 4 >40 ND 17. IA17
4.1 -6.417 0.536 2 2 2 >40 ND 18. IA18 4.89 -7.649 0.779 2 2 2
>40 ND 19. IA19 4.901 -7.39 0.737 4 4 4 >40 ND 20. IA20 4.314
-6.703 0.577 4 4 4 >40 ND 21. IA21 3.918 -4.257 0.239 1 1 1
>40 ND 22. IA22 4.757 -6.862 0.654 4 4 4 >40 ND 23. IA23 5.02
-7.417 0.753 4 4 4 >40 ND 24. IA24 4.085 -4.461 0.27 1.0 1.0 1.0
>40 >10 25. IA25 5.239 -7.628 0.732 0.12 0.12 0.12 >40
>10 26. IA26 4.365 -6.692 0.489 0.5 0.5 0.5 >40 >10 27.
IA27 5.05 -7.479 0.68 0.25 0.25 0.25 >40 >10 28. IA28 3.666
-3.153 -0.027 0.12 0.12 0.12 >40 >10 29. IA29 4.287 -6.48
0.553 32 32 32 >40 >10 30. IA30 4.993 -7.473 0.834 32 32 32
>40 >10 31. IA31 4.654 -6.889 0.68 0.25 0.25 0.25 >40
>10 32. IA32 5.334 -7.727 0.946 0.12 0.12 0.12 >40 >10 33.
IA33 5.25 -7.791 0.741 0.12 0.12 0.12 >40 >10 34. IA34 3.85
-3.45 0.003 0.12 0.12 0.12 >40 >10 35. IA35 4.597 -4.661
0.284 2 2 2 >40 ND 36. IA36 3.88 -3.548 0.014 2 2 2 >40 ND
37. IA37 4 -4.242 0.228 4 4 4 >40 ND 38. IA38 4.972 -7.524 0.835
4 4 4 >40 ND 39. IA39 4.835 -5.319 0.375 1.0 1.0 1.0 >40
>10 40. IA40 3.893 -4.655 0.251 4.0 4.0 4.0 >40 >10 41.
IA41 4.955 -5.495 0.403 2 2 2 >40 >10 42. IA42 4.327 -5.864
0.396 2 2 2 >40 >10 43. IB1 2.807 -5.114 0.146 2 2 2 >40
ND 44. IB2 3.812 -6.208 0.383 2 2 2 >40 ND 45. IB3 2.971 -5.282
0.257 4 4 4 >40 ND 46. IB4 3.036 -5.42 0.191 4 4 4 >40 ND 47.
IB5 3.645 -6.147 0.364 1 1 1 >40 ND 48. IB6 3.486 -6.037 0.444 2
2 2 >40 ND 49. IB7 3.19 -5.545 0.11 2 2 2 >40 ND 50. IB8
3.817 -6.394 0.289 4 4 4 >40 ND 51. IB9 3.272 -5.749 0.237 4 4 4
>40 ND 52. IB10 3.932 -6.222 0.296 1 1 1 >40 ND 53. IC1 3.89
-5.041 0.435 0.06 0.12 0.12 >40 >10 54. IC2 4.862 -7.334
0.923 2 2 2 >40 >10 55. IC3 4.621 -6.96 0.706 0.25 0.25 0.25
>40 >10 56. IC4 4.395 -6.685 0.661 2 2 2 >40 >10 57.
IC5 5.187 -7.898 0.907 1.0 1.0 1.0 >40 >10 58. IC6 4.511
-7.027 0.799 1.0 1.0 1.0 >40 >10 59. IC7 4.228 -6.461 0.596
0.5 1.0 1.0 >40 >10 60. IC8 4.425 -6.793 0.671 2 2 2 >40
ND 61. IC9 3.455 -5.814 0.326 2 2 2 >40 ND 62. IC10 5.336 -7.864
0.923 0.5 0.5 0.5 >40 >10 63. IC11 4.377 -6.588 0.651 32 32
32 >40 >10 64. IC12 5.101 -7.442 0.905 2 2 2 >40 >10
65. IC13 5.552 -8.029 0.871 0.12 0.12 0.12 >40 >10 66. IC14
4.52 -6.515 0.558 0.06 0.12 0.12 >40 >10 67. IC15 5.288
-7.631 0.795 0.25 0.5 0.5 >40 >10 68. IC16 4.397 -5.588 0.441
0.5 0.5 0.5 >40 >10 69. IC17 4.768 -7.19 0.749 0.5 0.5 0.5
>40 >10 70. IC18 5.311 -7.74 0.966 0.25 0.25 0.25 >40
>10 71. IC19 4.946 -7.198 0.813 2 2 2 >40 ND 72. IC20 5.65
-7.989 1.078 2 2 2 >40 ND 73. IC21 4.152 -5.241 0.391 4 4 4
>40 ND 74. IC22 4.732 -6.672 0.578 0.12 0.12 0.12 >40 >10
75. IIA1 3.213 -6.09 0.241 2 2 2 >40 >10 76. IIA2 3.621
-6.632 0.458 0.5 0.5 0.5 >40 >10 77. IIA3 3.942 -7.115 0.447
0.12 0.12 0.12 >40 >10 78. IIA4 3.286 -6.296 0.354 0.06 0.06
0.06 >40 >10 79. IIA5 3.05 -5.868 0.205 1.0 1.0 1.0 >40
>10 80. IIA6 4.107 -7.19 0.463 0.5 0.5 0.5 >40 >10 81.
IIA7 4.064 -6.742 0.511 2 2 2 >40 ND 82. IIA8 4.948 -7.646 0.712
2 2 2 >40 ND 83. IIA9 4.18 -6.784 0.54 4 4 4 >40 ND 84. IIA10
4.932 -7.902 0.748 4 4 4 >40 ND 85. IIB1 2.612 -5.191 0.101 2 2
2 >40 ND 86. IIB2 3.445 -6.106 0.212 2 2 2 >40 ND 87. IIB3
3.274 -6.027 0.195 2 2 2 >40 ND 88. IIB4 2.116 -2.889 -0.418 4 4
4 >40 ND 89. IIB5 2.825 -4.754 -0.09 4 4 4 >40 ND 90. IIB6
3.497 -5.606 0.016 1 1 1 >40 ND 91. IIC1 2.974 -5.094 -0.037 1 1
1 >40 ND 92. IIC2 3.396 -5.809 0.03 2 2 2 >40 ND 93. IIC3
3.66 -6.199 0.111 8.0 8.0 8.0 >40 >10 94. IIC4 4.16 -6.499
0.222 2 2 2 >40 >10 95. IIC5 1.911 -4.717 -0.45 2.0 2.0 2.0
>40 >10 96. IIC6 2.179 -4.335 -0.472 2.0 2.0 2.0 >40
>10 97. IIC7 1.825 -3.619 -0.419 1.0 1.0 1.0 >40 >10 98.
IIC8 3.552 -5.818 0.252 0.5 0.5 0.5 >40 >10 99. IIC9 1.471
-3.158 -0.565 1.0 1.0 1.0 >40 >10 100. IIC10 0.698 -2.153
-1.007 0.5 0.5 0.5 >40 >10 ND: not determined MDR = M.
tuberculosis resistant to isoniazid and rifampicin XDR = M.
tuberculosis resistant to isoniazid, rifampicin, amikacin and
moxifloxacin
Example 14
In Vivo Pharmacokinetics
[0580] Compounds were administered orally to mice (Balb/c mice) at
a dose of 5 mg/kg as a suspension in 0.5% CMC and Tween 80. Samples
were derived from plasma at different time points i.e. 0.16 h, 0.5
h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h, which were then analysed by
LC-MS/MS to generate the required pharmacokinetic parameters.
[0581] Result:
[0582] Four compounds IA25, IA33, IC13 and IC14 were studied for
the pharmacokinetic properties along with OPC-67683 (clinical
candidate of Otsuka). Two compounds IA25 (C.sub.max 1023 nM and AUC
13960.67 nM*hr), IC13 (C.sub.max 2533.81 nM and AUC 33679 nM*hr)
showed improved pharmacokinetic properties compared to OPC-67683
(C.sub.max 668 nM and AUC 9322.33 nM*hr). The detailed
pharmacokinetic properties for the four compounds are shown in
Table 11.
TABLE-US-00010 TABLE 11 S. No PK-parameters OPC-67683 IA25 IA33
IC13 IC14 1 C.sub.MAX (nM) 668.01 1023.90 594.88 2533.81 352.65 2
T.sub.max (hr) 2.00 2.00 2.00 2.00 2.00 3 AUC (nM*hr) 9322.33
13960.67 3952.00 33679.00 1554.67 4 Ka (hr) 1.09 1.71 0.478 1.21
1.056 5 t.sub.1/2absorption (hr) 0.64 0.41 1.448 0.57 0.656 6
CL.sub.B (L/kg/hr) 0.0043 0.007 0.072 0.0033 0.202 7 Vdarea(L/kg)
0.76 0.36 0.25 0.13 1.54
Example 15
Combination Studies
[0583] The efficacy of compounds IA25 and IIA3 (conc range 4
.mu.g/ml to 0.007 .mu.g/ml) in combination with currently used
anti-TB drugs such as rifampicin, isoniazid and ethambutol (each
drug tested at conc range 4 .mu.g/ml to 0.007 mg/ml), wherein the
ratio of drugs was ranging between 0.1% to 50%, was determined in
vitro using checkerboard method. The checkerboard procedure was
performed based on the MIC values by the broth microdilution
method. The checkerboard method was performed in 96 well U bottom
microtitre plates. 100 microliters of 4.times. concentration of
drug was added to first column of the plate. 50 microliters from
first column was transferred to second column and was serially
diluted in horizontal manner upto column 10 of the plate. Seven
dilutions of 4.times. concentration of compound were prepared in
eppendorfs and fifty microliters of each concentration was added
vertically starting from eleventh column of row eight to row second
of the plate. First row of the plate served as drug control. 100
microliters of 1:10 diluted of 1 Mc Farland inoculum was added to
each well of the plate. Plates were then incubated at 37.degree. C.
for 14 days. MIC of drug alone and in presence of compound and vice
versa was observed visually. The level of synergy was determined by
calculating the fractional inhibitory concentration (FIC) index
based on the following formula: FIC of drug A=MIC of drug A in
combination/MIC of drug A alone; FIC of drug B=MIC of drug B in
combination/MIC of drug B alone; and FIC index=FIC of drug A+FIC of
drug B. Results of FIC index were interpreted as follows:
.ltoreq.0.5: synergy, >0.5 to 0.75: partial synergy, >0.75 to
1.0: additive effect, >1.0 to 4.0: indifference, and >4.0:
antagonism. The FIC index value for each concentration of two-drug
combination was calculated and the minimum value was adopted.
[0584] Result:
[0585] The efficacy of compound IA25 in combination with known anti
tuberculosis drugs has shown additive effect with rifampicin,
synergistic effect with isoniazid and additive effect with
ehambutol. Similarly compound IIA3 in combination with known anti
tuberculosis drugs has shown synergistic effect with rifampicin,
additive effect with isoniazid and additive effect with ehambutol
and the detailed results of combination studies given in Table
10.
TABLE-US-00011 TABLE 10 FIC FIC Index (MIC combination/ (FIC A + S.
No Combinations MIC MIC alone) FIC B) Observations 1. MIC of
Rifampicin alone 0.12 FIC A = 0.25 0.5 Synergistic MIC of
Rifampicin with IIA3 0.06 MIC of IIA3 0.5 FIC B = 0.25 MIC of IIA3
with Rifampicin 0.12 2. MIC of INH alone 0.25 FIC A = 0.5 0.75
Additive MIC of INH with IIA3 0.12 MIC of IIA3 0.5 FIC B = 0.25 MIC
of IIA3 with INH 0.12 3. MIC of Ethambutol alone 1.0 FIC A = 0.5
0.75 Additive MIC of Ehambutol with IIA3 0.5 MIC of IIA3 0.5 FIC B
= 0.25 MIC of IIA3 with Ehambutol 0.12 4. MIC of Rifampicin alone
0.12 FIC A = 0.25 0.75 Additive MIC of Rifamipicin with IA25 0.03
MIC of IA25 0.12 FIC B = 0.5 MIC of IA25 with Rifampicin 0.06 5.
MIC of INH alone 0.25 FIC A = 0.25 0.5 Synergistic MIC of INH with
IA25 0.06 MIC of IA25 0.12 FIC B = 0.25 MIC of IA25 with INH 0.03
6. MIC of Ethambutol alone 1.0 FIC A = 0.25 0.75 Additive MIC of
Ehambutol with IA25 0.25 MIC of IA25 0.12 FIC B = 0.5 MIC of IA25
with Ehambutol 0.06 IIA3 & IA25 has shown synergistic or
additive activity with rifampicin, INH and ethambutol.
ADVANTAGE OF THE INVENTION
[0586] Compounds of formula I and II of general formula 1 have
shown potent MIC against H37Rv TB as well MDR-TB and XDR-TB.
[0587] Compounds of the general formula 1 exhibit promising
pharmaco-kinetics properties with acceptable C.sub.max and AUC.
[0588] Compounds of the formula I and II of general formula 1 shows
synergistic as well as additive affect in combination studies with
other first line anti-TB agents such as isoniazid, rifampicine and
ethambutol.
* * * * *